Synthesis of Glycoborine, Glybomine A and B, the Phytoalexin Carbalexin A and the β-Adrenoreceptor Antagonists Carazolol and Carvedilol

Article abstract of DOI:10.1002/chem.201604002

We describe a regioselective synthesis of 4- or 5-substituted carbazoles by oxidative cyclisation of meta-oxygen-substituted N-phenylanilines. Using the regiodirecting effect of a pivaloyloxy group, we prepared 4-hydroxycarbazole, a precursor for the enantiospecific synthesis of the β-adrenoreceptor antagonists (?)-(S)-carazolol (5) and (?)-(S)-carvedilol (6). Regioselective palladium(II)-catalysed cyclisation of different diarylamines led to total synthesis of glycoborine (7) and the first total syntheses of the phytoalexin carbalexin A (8), glybomine A (9) and glybomine B (10). For glybomine B (10), a 5-hydroxycarbazole was converted into the corresponding triflate and utilized for introduction of a prenyl substituent.

Full text of DOI:10.1002/chem.201604002

DOI: 10.1002/chem.201604002
Full Paper
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Alkaloids
Synthesis of Glycoborine, Glybomine A and B, the Phytoalexin
Carbalexin A and the b-Adrenoreceptor Antagonists Carazolol and
Carvedilol**
Christian Brꢀtting, Ronny Hesse, Anne Jꢁger, Olga Kataeva, Arndt W. Schmidt, and
Hans-Joachim Knçlker*[a]
Abstract: We describe a regioselective synthesis of 4- or 5-
substituted carbazoles by oxidative cyclisation of meta-
oxygen-substituted N-phenylanilines. Using the regiodirect-
ing effect of a pivaloyloxy group, we prepared 4-hydroxycar-
bazole, a precursor for the enantiospecific synthesis of the
b-adrenoreceptor antagonists (À)-(S)-carazolol (5) and (À)-
(S)-carvedilol (6). Regioselective palladium(II)-catalysed cycli-
sation of different diarylamines led to total synthesis of gly-
coborine (7) and the first total syntheses of the phytoalexin
carbalexin A (8), glybomine A (9) and glybomine B (10). For
glybomine B (10), a 5-hydroxycarbazole was converted into
the corresponding triflate and utilized for introduction of
a prenyl substituent.
Introduction
The palladium(II)-catalysed oxidative cyclisation of diarylamines
is one of the most convenient and versatile methods for the
construction of the carbazole skeleton.[1,2] The reaction pro-
ceeds via initial formation of a dibenzo[1,4]palladazine by
double CÀH bond activation and subsequent reductive elimi-
nation of a palladium(0) species.[3] This mechanism was postu-
lated already in 1975 by ꢂkermark and co-workers.[4] In 2012,
we have described the first isolation and characterisation of
a dibenzo[1,4]palladazine as intermediate of the reductive
elimination and its conversion into the corresponding carba-
zole.[5] In the course of our studies, we have shown that the
palladium(II)-induced oxidative cyclisation of a m-(pivaloyloxy)-
substituted diarylamine 1 preferentially leads to the 4-oxygen-
ated carbazole 3 (Scheme 1).
Scheme 1. Palladium(II)-catalysed oxidative cyclisation of meta-pivaloyloxy-
substituted diarylamines (L=ligand).
The regioselectivity most likely results from stabilisation of
the intermediate dibenzo[1,4]palladazine 2 by coordination of
the neighbouring pivaloyloxy group. Thus, 4-oxygenated car-
bazoles, which frequently have been observed as side-products
in the oxidative cyclisation of meta-oxygen-substituted diaryl-
amines, are becoming the major products.[2h–j,6,7] Herein, we
describe the application of the pivaloyloxy-directed CÀH bond
activation to the regioselective synthesis of a range of 4- and
5-substituted carbazole alkaloids (Figure 1).
As synthetic targets served the non-natural b-adrenorecep-
tor antagonists carazolol (5) und carvedilol (6) which were first
described in 1974 and 1979, respectively.[8] Although both
agents are usually administered in racemic form, we decided
to synthesise the more active (S)-isomers.[9] Furthermore, we
envisaged a total synthesis of the natural products 7-10 which
have been isolated from different plants of the genus Glyco-
smis. Glycoborine (7) was first obtained in 2001 by Chakravarty
et al. from the roots of Glycosmis arborea.[10,11] In the course of
structural elucidation, the same group also described the first
synthetic approach to that compound. Compound 7 has also
been isolated by Laphookhieo (who named it glycrophyl-
amine)[12] and has been obtained by total synthesis by Kuethe,
Tamariz, and Kꢀrti et al.[13] In 2014, we obtained 5-methoxy-3-
[a] C. Brꢀtting, Dr. R. Hesse, A. Jꢁger, Dr. O. Kataeva, Dr. A. W. Schmidt,
Prof. Dr. H.-J. Knçlker
Department Chemie,Technische Universitꢁt Dresden
Bergstraße 66, 01069 Dresden (Germany)
Fax: (+49)351-463-37030
E-mail: hans-joachim.knoelker@tu-dresden.de
[**] See reference [32].
Supporting information for this article can be found under
http://dx.doi.org/10.1002/chem.201604002.
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Table 1. Optimisation of the temperature for the oxidative cyclisation of
12.
Scale
[mg]
T
[8C]
Yield [%]
14
12
14+12[b]
100
100
100
100
100
100
219
400
800
40
50
60
70
75
80
75
75
75
26
45
70
84
87
64
85
85
84
69
50
25
8
4
0
3
4
4
95
95
95
92
91
64
88
89
88
[a] Reagents and conditions: Pd(OAc)2 (15 mol%), AcOH, air, 22 h. [b] Re-
mainder of material was lost due to decomposition.
We have shown before that prolonged exposure of carba-
zoles to palladium(II) salts at high temperatures leads to de-
composition.[17a,b] On the other hand, at lower temperatures
the reaction rate decreases and below a certain substrate-spe-
cific temperature, the oxidative cyclisation cannot be achieved
anymore.[17c] In the present case, we determined that conduct-
ing the cyclisation at 758C led to the best results and the de-
sired carbazol-4-yl pivalate 14 was regioselectively obtained in
87% yield along with 4% reisolated starting material. At lower
reaction temperatures, a higher proportion of unreacted start-
ing material could be reisolated. At 808C complete conversion
occurred, but 14 was obtained in only 64% yield, probably
due to decomposition of the product.
Figure 1. Adrenoreceptor blocking agents (À)-(S)-carazolol (5) and (À)-(S)-
carvedilol (6) and naturally occurring 5-substituted carbazole alkaloids.
methylcarbazole (7) as by-product in the palladium(II)-cata-
lysed oxidative cyclisation of N-phenyl-3-methoxyaniline en
route to various pyrano[3,2-a]carbazole alkaloids.[2i] Carbalexin
A (8) has been obtained in 2001 by Greger et al. who conduct-
ed experiments regarding plant responses to physical stress.[14]
In the course of these studies, leaves of Glycosmis parviflora
had been infected with the fungus Botrytis cinerea. In response
to the infection, various new compounds (inter alia compound
8) were formed which had not been detected in the plant
before. Glybomine A (9) and B (10) were isolated by Itoigawa
and Furukawa et al. from the stem of Glycosmis arborea.[15] At
first glance, glybomine B (10) does not seem to fit into this
study since it does not bear an oxygen substituent at C-4 or C-
5. However, we envisaged the introduction of the prenyl group
by a palladium(0)-catalysed coupling reaction of a carbazol-4-yl
triflate, which would be accessible from the corresponding 4-
(pivaloyloxy)carbazole. To the best of our knowledge, no syn-
thetic access to the carbazole alkaloids 8–10 has been report-
ed so far, except for a transformation of a carbalexin C precur-
sor into glybomine B (10) previously achieved in our group.[16]
We attempted to isolate the putative intermediate 13, either
as acetic acid (L=AcOH) or as pyridine complex (L=pyridine).
However in agreement with our previous observations, the k3-
palladium(II) complexes 13 proved to be very unstable and
could be identified only by their mass spectra.[5] The isotopic
patterns of the detected mass fragments perfectly match the
calculated values (Figures 2 and 3).
The carbazolyl pivalate 14 was then transformed into the
desired pharmaceutical agents 5 and 6. Reductive cleavage of
Results and Discussion
Our approach to (S)-carazolol (5) and (S)-carvedilol (6) relied on
regioselective palladium(II)-catalysed oxidative cyclisation of
the diarylamine 12 which was obtained in high yield by Buch-
wald–Hartwig amination of 3-bromophenyl pivalate (11) using
aniline as nucleophile (Scheme 2). Oxidative cyclisation was
triggered by heating a solution of 12 and catalytic amounts of
palladium(II) acetate in acetic acid under air. For the present
substrate, the reaction temperature was carefully optimised
(Table 1).
Figure 2. ESI-MS: Calculated isotopic distribution and peaks of complex frag-
ment [13+HÀL]+ (L=AcOH).
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the pivaloyl group provided 4-hydroxycarbazole (15). Coupling
of 15 and (R)-epichlorohydrin provided 16, most likely by initial
attack of the carbazole oxygen atom at the terminal carbon
atom of the epoxide and subsequent intramolecular displace-
ment of the chloride atom. Reaction of 16 and isopropylamine
finally provided (À)-(S)-carazolol (5) in 5 steps and 62% yield.
The absolute stereochemistry was proven by single-crystal X-
ray analysis of (À)-(S)-1-bromocarazolol (18) (Figure 4). The
latter was obtained by regioselective bromination of 16 to the
known 1-bromocarbazole 17[18] followed by reaction with iso-
propylamine as described for the transformation of 16 into 5.
(À)-(S)-Carvedilol (6) was synthesised by epoxide opening of
16 using 2-(2-methoxyphenoxy)ethanamine as nucleophile.
Compounds 5 and 6 have been fully characterised and their
optical and spectroscopic data are in good agreement with
those reported in the literature.[8d,h]
Scheme 2. Synthesis of (À)-(S)-carazolol (5) and (À)-(S)-carvedilol (6). (a) Ani-
line (1.2 equiv), Pd(OAc)2 (5 mol%), XPhos (10 mol%), Cs2CO3 (1.2 equiv),
PhMe, reflux, 22 h (97%); (b) Pd(OAc)2 (15 mol%), AcOH, air, 758C, 22 h
(87%); (c) LiAlH4 (3.0 equiv), THF, RT, 15 min (97%); (d) (R)-epichlorohydrin
(1.02 equiv), NaOH (1.05 equiv), DMSO/H2O (2:1), RT, 7.5 h (91%); (e) iPrNH2
(15 equiv), MeOH, 658C, 2 h (83%); (f) NBS (1.03 equiv), HBr (cat.; aqueous,
48%), MeCN, RT, 1.5 h (70%); (g) iPrNH2 (15 equiv), MeOH, 658C, 1.5 h (91%);
(h) 2-(2-methoxyphenoxy)ethanamine (2.0 equiv), iPrOH, reflux, 2 h (76%).
XPhos=2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl.
Figure 4. Molecular structure of (À)-(S)-1-bromocarazolol (18) in the crystal.
ORTEP plot showing thermal ellipsoids at the 50% probability level.
For the synthesis of glycoborine (7), we first prepared diaryl-
amine 19 by Buchwald-Hartwig coupling of bromophenyl piva-
late 11 and para-toluidine (Scheme 3). Oxidative cyclisation
was most reliably accomplished by microwave heating of an
acetic acid solution of the diarylamine 19, catalytic amounts of
palladium(II) acetate and cupric acetate to afford carbazol-5-yl
pivalate 20 in 69% yield. Reductive cleavage of the pivaloyl
group and subsequent methyl ether formation provided glyco-
borine (7) in four steps and 47% overall yield. The structure of
compound 7 was confirmed by X-ray analysis (Figure 5).
Carbalexin A (8) and glybomine A (9) were synthesised
using the same strategy for construction of the carbazole
framework (Scheme 4). The required diarylamine 24 was ob-
tained in three steps from 2-methyl-5-nitrophenol (22) via a se-
quence of triisopropylsilyl (TIPS) ether formation, reduction of
the nitro group and palladium(0)-catalysed coupling with the
bromophenyl pivalate 11. Oxidative cyclisation under micro-
wave conditions as described for the synthesis of glycoborine
Figure 3. ESI-MS: Calculated isotopic distribution and peaks of complex
[13+H]+ (L=pyridine).
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Scheme 3. Synthesis of glycoborine (7). (a) p-Toluidine (1.2 equiv), Pd(OAc)2
(6 mol%), rac-BINAP (6 mol%), Cs2CO3 (1.2 equiv), PhMe, reflux, 24 h (82%);
(b) Pd(OAc)2 (15 mol%), Cu(OAc)2 (2.5 equiv), AcOH, microwave (300 W),
1308C, 3 h (69%); (c) LiAlH4 (4.0 equiv), THF, RT, 45 min (92%); (d) Me2SO4
(5.0 equiv), K2CO3 (2.0 equiv), acetone, reflux, 20 h (91%). BINAP=2,2’-bis(di-
phenylphosphino)-1,1’-binaphthalene.
Scheme 4. Synthesis of carbalexin A (8) and glybomine A (9). (a) 1. TIPSCl
(1.3 equiv), ImH (2.0 equiv), DMF, RT, 21 h; 2. Fe (powder, 10 equiv), AcOH,
408C, vacuum (600 mbar), 4 h (90%, two steps); (b) 11 (1.0 equiv), 23
(1.2 equiv), Pd(OAc)2 (5 mol%), XPhos (10 mol%), Cs2CO3 (1.2 equiv), PhMe,
reflux, 23 h (96%); (c) Pd(OAc)2 (15 mol%), Cu(OAc)2 (2.5 equiv), AcOH, mi-
crowave (300 W), 1308C, 3 h (81%); (d) LiAlH4 (4.0 equiv), THF, RT, 25 min
(92%); (e) Me2SO4 (5.0 equiv), K2CO3 (2.0 equiv), acetone, reflux, 20 h (90%);
(f) TBAF (1.5 equiv), THF, RT, 10 min (100%); (g) Me2SO4 (5.0 equiv), K2CO3
(2.0 equiv), acetone, reflux, 20 h (86%); (h) TBAF (1.2 equiv), THF, RT, 10 min;
(i) Me2SO4 (8.0 equiv), K2CO3 (3.0 equiv), acetone, reflux, 21 h (74%, 2 steps).
Figure 5. Molecular structure of glycoborine (7) in the crystal. ORTEP plot
showing thermal ellipsoids at the 50% probability level.
(7) provided the desired carbazolyl pivalate 25 in 81% yield.
Reductive cleavage of the pivaloyl group led to the 5-hydroxy-
carbazole 26. O-Methylation with dimethyl sulfate and finally
fluoride-mediated silyl ether cleavage led to carbalexin A (8) in
six steps and 58% overall yield.
Three different routes were explored towards glybomine A
(9). First, simple O-methylation of carbalexin A (8) provided
glybomine
A (9) in seven steps and 50% overall yield
(Scheme 4). The second route relied on the hydroxycarbazole
26. Silyl ether cleavage to the oxygen sensitive dihydroxycar-
bazole 28 followed by double methyl etherification led to gly-
bomine A (9) in 6 steps and 48% overall yield. In the short
third route, the carbazole skeleton was constructed using the
aniline 29 as starting material (Scheme 5).
This approach avoids usage of the TIPS protecting group
and thus was expected to deliver the natural product 9 more
efficiently. Buchwald–Hartwig amination of 3-bromophenyl piv-
alate (11) with 29 provided the diarylamine 30 almost quanti-
tatively. However, oxidative cyclisation of 30 under the same
conditions as described above (15 mol% Pd(OAc)2, 2.5 equiv
Scheme 5. Third route to glybomine A (9). (a) 11 (1.0 equiv), 29 (1.2 equiv),
Pd(OAc)2 (5 mol%), XPhos (10 mol%), Cs2CO3 (1.2 equiv), PhMe, reflux, 23 h
(98%); (b) Pd(OAc)2 (15 mol%), Cu(OAc)2 (2.5 equiv), AcOH, microwave
(300 W), 1308C, 3 h (31: 50%; 32: 13%); (c) LiAlH4 (4.0 equiv), THF, RT, 30 min
(82%); (d) Me2SO4 (5.0 equiv), K2CO3 (2.0 equiv), acetone, reflux, 20 h (100%).
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Cu(OAc)2, acetic acid, microwave, 300 W, 1308C, 3 h) provided
the desired 2,5-dioxygenated carbazole 31 together with the
undesired 2,7-dioxygenated regioisomer 32 (ratio of 31/32 =
3.8:1; 63% combined yield). Separation of the desired 2,5-di-
oxygenated carbazole 31 by flash chromatography followed
by ester cleavage and formation of the methyl ether provided
glybomine A (9) in four steps and 40% yield. Despite the lack
of regioselectivity in the oxidative cyclisation, the route depict-
ed in Scheme 5 provides the shortest access to glybomine A
(9).
For our approach to glybomine B (10) we envisaged a transi-
tion metal-catalysed coupling of a prenylmetal precursor and
a carbazol-4-yl triflate. Therefore, we first decided to develop
conditions suitable for prenylation using carbazol-4-yl triflate
(34) as model compound (Scheme 6).
palladium provided 4-prenylcarbazole (35) in 40% yield along
with starting material (37%). Prolonged exposure of 34 to the
reaction conditions did not improve the outcome. Increasing
the amount of prenylindium to 5 equivalents afforded the cou-
pling product 35 in up to 62% yield.
Then, we focused on the total synthesis of glybomine B (10)
(Scheme 7). Buchwald–Hartwig coupling of bromoarene 36
and the aniline 23, which was already used as starting material
for our route to glybomine A (8) (see above), led to the diaryl-
amine 37. Subsequent palladium(II)-catalysed oxidative cyclisa-
tion of compound 37 under microwave conditions using acetic
acid as solvent provided the carbazoles 38 and 39 as a mixture
of regioisomers in a ratio of 1.4:1 in favour of the desired
isomer 38 (combined yield: 76%). Using pivalic acid as solvent
for the cyclisation led to increased formation of the undesired
regioisomer 39 (Table 3), a potential precursor for synthesis of
koenigine or koenigicine.[2r] Selective cleavage of the pivaloyl
group of the 2,5,6-trioxygenated carbazole 38 by treatment
with lithium aluminium hydride followed by esterification of
40 with triflic anhydride provided the carbazolyl triflate 41 in
high yield. Surprisingly, neither the treatment of 41 with an
excess of prenyl bromide and tetracarbonylnickel,[2c,19,20] nor
the palladium-catalysed coupling with in situ generated preny-
lindium,[21] nor the coupling with tert-prenylboronic acid pina-
[22]
col ester in the presence of catalytic amounts of Pd(dba)2
Scheme 6. Synthesis of 4-prenylcarbazole (35). (a) Tf2O (1.2 equiv), NEt3
(1.1 equiv), CH2Cl2, 08C, 15 min (92%); (b) prenyl bromide (5.4 equiv), indium
(powder, 5.0 equiv), Pd(PPh3)4 (10 mol%), LiCl (3.0 equiv), DMF, 1008C, 3 h
(62%).
provided the desired product 42 but led largely to the recov-
ery of starting material. However, prolonged heating of 41 and
prenylboronic acid pinacol ester in presence of tetrakis(triphen-
ylphosphine)palladium and sodium hydroxide as base in a bi-
phasic toluene-water mixture provided the desired prenylcar-
bazole 42 in 58% yield.[23] The structure of 42 was unequivo-
cally confirmed by single crystal X-ray analysis (Figure 6). Final-
ly, removal of the silyl protecting group provided glybomine B
(10) in 7 steps and 18% overall yield based on commercially
available compounds.
Compound 34 was easily prepared from 4-hydroxycarbazole
(15), the intermediate for carazolol (5) and carvedilol (6) (see
Scheme 2). Reaction of 34 with overstoichiometric amounts of
prenyl bromide and tetracarbonylnickel,[19] a very reliable
method for prenylation of bromocarbazoles,[1g,2c,20] afforded 4-
prenylcarbazole (35) in 55% yield and 35% of starting material
(Table 2). To the best of our knowledge, this is the first report
Table 3. Comparison of acetic acid and pivalic acid as solvent for the oxi-
dative cyclisation of 37.
Table 2. Metal-mediated prenylation of carbazol-4-yl triflate (34).
Reaction conditions[a]
35, Yield
Conditions
Yield[%]
38 39
44 32
[%][b]
prenyl bromide (9.1 equiv), Ni(CO)4 (31 equiv), DMF, 608C, 4 h 55
Pd(OAc)2 (20 mol%), Cu(OAc)2 (2.5 equiv), AcOH, microwave
(300 W), 1308C, 30 min
Pd(OAc)2 (15 mol%), Cu(OAc)2 (2.5 equiv), PivOH, microwave
(300 W), 1308C, 2 h
prenyl bromide (2.0 equiv), In (1.5 equiv), Pd(PPh3)4
(10 mol%), LiCl (3.0 equiv), DMF, 1008C, 3 h
prenyl bromide (2.0 equiv), In (1.5 equiv), Pd(PPh3)4
(10 mol%), LiCl (3.0 equiv), DMF, 1008C, 15 h
40
38 59
40
prenyl bromide (5.4 equiv), In (5 equiv), Pd(PPh3)4 (10 mol%), 62
LiCl (3.0 equiv), DMF, 1008C, 3 h
Conclusion
[a] All reactions were stirred until TLC indicated no further conversion.
[b] Varying amounts (25–40%) of starting material (34) were recovered.
We have developed a protocol for the regioselective synthesis
of 4-oxygenated carbazoles by oxidative cyclisation of meta-
pivaloyloxy-substituted diarylamines. The resulting carbazol-4-
yl pivalates were converted into biologically active carbazole
derivatives. The b-adrenoreceptor antagonists (À)-(S)-carazolol
(5) and (À)-(S)-carvedilol (6) were synthesised using carbazol-4-
yl pivalate (14) as intermediate. The connectivity and absolute
configuration of (À)-(S)-carazolol (5) were confirmed by single
of a nickel(0)-mediated allylation of an aryl triflate. We then
turned our attention to an indium-mediated protocol, success-
fully used by She et al. for prenylation of an indolyl triflate.[21]
Treatment of 34 with 1.5 equivalents of prenylindium in the
presence of catalytic amounts of tetrakis(triphenylphosphane)-
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to glybomine B (10) demonstrates that the present method
not only provides a regioselective access to 4-oxygenated car-
bazoles but can be also applied to other 4-functionalised deriv-
atives.
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 sol-
vent purification system (MBraun-SPS). Petroleum ether (PE) used
refers to the hydrocarbon mixture with a boiling range of 40–658C.
Pd(OAc)2 was recrystallized from glacial AcOH. All other chemicals
were used as received from commercial sources. Flash chromatog-
raphy 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 mea-
sured on a Gallenkamp MPD 350 melting point apparatus. Fluores-
cence spectra were recorded on a Varian Cary Eclipse spectrometer.
Ultraviolet spectra were recorded on a PerkinElmer 25 UV/Vis spec-
trometer. IR spectra were recorded on a Thermo Nicolet Avatar 360
FT-IR spectrometer using the ATR method (Attenuated Total Reflec-
tance). NMR spectra were recorded on Bruker DRX 500 and Avance
III 600 spectrometers. Chemical shifts d are reported in parts per
million with the solvent signal as internal standard. Standard ab-
breviations were used to denote the multiplicities of the signals.
Mass spectra were recorded on a Finnigan MAT-95 spectrometer
(electron impact, 70 eV) or by GC/MS-coupling using an Agilent
Technologies 6890 N GC System equipped with a 5973 Mass Selec-
tive Detector (electron impact, 70 eV). ESI-MS spectra were record-
ed on an Esquire LC with an ion trap detector from Bruker. Positive
and negative ions were detected. Elemental analyses were mea-
sured on an EuroVector EuroEA3000 elemental analyser. X-ray crys-
tal structure analyses were performed with a Bruker-Nonius Kappa
CCD that was equipped with a 700 series Cryostream low tempera-
ture device from Oxford Cryosystems. SHELXS-97,[24] SADABS ver-
sion 2.10,[25] SHELXL-97,[26] POV-Ray for Windows version
3.7.0.msvc10.win64, and ORTEP-3 for Windows[27] were used as
software.
Scheme 7. Synthesis of glybomine B (10). (a) 23 (1.2 equiv), Pd(OAc)2
(5 mol%), XPhos (10 mol%), Cs2CO3 (1.2 equiv), PhMe, reflux, 19.5 h (92%);
(b) Pd(OAc)2 (20 mol%), Cu(OAc)2 (2.5 equiv), AcOH, microwave (300 W),
1308C, 30 min (38: 44%; 39: 32%); (c) LiAlH4 (3.0 equiv), THF, 08C, 15 min
(91%); (d) Tf2O (1.2 equiv), NEt3 (1.1 equiv), CH2Cl2, 08C, 10 min (89%);
(e) prenylboronic acid pinacol ester (2.0 equiv), Pd(PPh3)4 (10 mol%), NaOH
(20 equiv), H2O/PhMe (1:1), 908C, 21 h (58%); (f) TBAF (1.5 equiv), THF, 08C,
5 min (95%).
3-Bromophenyl pivalate (11): Pivaloyl chloride (6.4 mL, 6.3 g,
52 mmol) was added to a solution of 3-bromophenol (6.00 g,
34.7 mmol), triethylamine (14.5 mL, 10.5 g, 104 mmol) and DMAP
(84.7 mg, 0.694 mmol) in dichloromethane (250 mL) and the mix-
ture was stirred at room temperature for 19 h. The solution was
washed with saturated aqueous ammonium chloride solution, the
organic layer was dried (MgSO4) and the solvent was evaporated.
Purification by column chromatography (silica gel; pentane/ethyl
acetate 25:1) provided bromophenyl pivalate 11 (8.90 g,
1
34.6 mmol, 100%) as colourless oil. H NMR (500 MHz, CDCl3): d=
1.34 (s, 9H), 7.01 (ddd, J=8.2, 2.2, 0.9 Hz, 1H), 7.21–7.26 (m, 2H),
7.35 ppm (ddd, J=8.0, 1.8, 0.9 Hz, 1H); 13C NMR and DEPT
(125 MHz, CDCl3): d=26.99 (3 CH3), 39.01 (C), 120.35 (CH), 122.21
(C), 124.97 (CH), 128.70 (CH), 130.32 (CH), 151.55 (C), 176.55 ppm
(C=O); MS (EI): m/z (%): 258 (7), 256 (7) [M]+, 174 (70), 172 (73), 85
(33), 57 (100). Further spectroscopic data: see ref. [28]
Figure 6. Molecular structure of O-(triisopropylsilyl)glybomine B (42) in the
crystal. ORTEP plot showing thermal ellipsoids at the 50% probability level.
crystal X-ray analysis of (À)-(S)-1-bromocarazolol (18). The ver-
satility of our method was further demonstrated by total syn-
thesis of the natural products glycoborine (7), carbalexin A (8),
glybomine A (9) and glybomine B (10). The spectroscopic data
of our synthetic compounds are in agreement with those re-
ported for the natural products. For the carbazole alkaloids 8,
9 and 10, we have reported the first total synthesis. Our route
3-(Phenylamino)phenyl pivalate (12): A solution of 11 (1.00 g,
3.89 mmol) in toluene (8 mL) was added over a period of 2 h to
a refluxing suspension of aniline (426 mL, 435 mg, 4.67 mmol), cae-
sium carbonate (1.52 g, 4.67 mmol), XPhos (185 mg, 0.389 mmol)
and palladium acetate (43.6 mg, 0.194 mmol) in toluene (32 mL).
The mixture was stirred and heated at reflux under argon for 20 h
(total reaction time: 22 h). The mixture was cooled to room tem-
&
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perature and filtered (Celiteꢄ; ethyl acetate). The solvent was
evaporated and the residue was purified by column chromatogra-
phy (silica gel; pentane/ethyl acetate 15:1) to provide diarylamine
12 (1.02 g, 3.79 mmol, 97%) as light yellow solid. M.p. 89–918C
(lit.: m.p. 87–898C);[29] 1H NMR (500 MHz, CDCl3): d=1.34 (s, 9H),
5.75 (brs, 1H), 6.59 (ddd, J=8.0, 2.1, 0.7 Hz, 1H), 6.75 (t, J=2.2 Hz,
1H), 6.88 (ddd, J=8.1, 2.1, 0.7 Hz, 1H), 6.96 (tt, J=7.3, 0.9 Hz, 1H),
7.07–7.09 (m, 2H), 7.22 (t, J=8.1 Hz, 1H), 7.26–7.30 ppm (m, 2H);
13C NMR and DEPT (125 MHz, CDCl3): d=27.12 (3 CH3), 39.04 (C),
110.28 (CH), 113.53 (CH), 114.44 (CH), 118.48 (2 CH), 121.56 (CH),
129.38 (2 CH), 129.93 (CH), 142.35 (C), 144.48 (C), 152.07 (C),
177.03 ppm (C=O); IR (ATR): n˜ =3370, 3028, 2969, 2869, 2056, 2030,
1725, 1699, 1651, 1594, 1528, 1488, 1398, 1321, 1279, 1235, 1144,
d=103.34 (CH), 105.13 (CH), 110.02 (CH), 111.74 (C), 119.70 (CH),
122.28 (C), 122.73 (CH), 125.13 (CH), 126.55 (CH), 138.80 (C), 141.36
(C), 151.82 ppm (C); IR (ATR): n˜ =3394, 3197, 3051, 2955, 2922,
2850, 2156, 2029, 1606, 1584, 1504, 1489, 1447, 1398, 1328, 1303,
1266, 1205, 1114, 1042, 998, 930, 840, 783, 751, 717, 652 cmÀ1; UV
(MeOH): l=224, 243, 251 (sh), 274 (sh), 284, 320, 333 nm; fluores-
cence (MeOH): lex =283 nm, lem =342, 356 nm; MS (EI): m/z (%):
183 (100) [M]+, 154 (56), 127 (13), 77 (11); elemental analysis (%)
calcd for C12H9NO: C 78.67, H 4.95, N 7.65; found: C 78.66, H 5.16,
N 7.34.
(+)-(S)-4-(Oxiran-2-ylmethoxy)carbazole (16): Aqueous sodium
hydroxide solution (1m, 1.33 mL, 1.33 mmol) and (R)-epichlorohy-
drin (0.11 mL, 0.12 g, 1.3 mmol) were added sequentially under
1128, 1030, 996, 960, 911, 890, 876, 863, 768, 745, 688, 617 cmÀ1
;
argon to
a
solution of 4-hydroxycarbazole (15) (233 mg,
UV (MeOH): l=284 nm; MS (EI): m/z (%): 269 (53) [M]+, 185 (100),
57 (41); elemental analysis (%) calcd for C17H19NO2: C 75.81, H 7.11,
N 5.20; found: C 75.81, H 7.21, N 5.15.
1.27 mmol) in DMSO (0.6 mL) and the mixture was stirred for 7.5 h.
Water was added and the mixture was extracted with diethyl ether
twice. The combined organic layers were dried (MgSO4) and the
solvent was evaporated. Purification of the residue by column
chromatography (silica gel; pentane/ethyl acetate 4:1) provided
the oxirane 16 (278 mg, 1.16 mmol, 91%) as colourless solid. M.p.
156–1598C (lit.: m.p. 163–1648C);[8d] [a]D20 = +61.1 (c=1, pyridine)
[lit.: +64.4 (c=1, pyridine)];[8d] 1H NMR (500 MHz, CDCl3): d=2.89
(dd, J=4.9, 2.6 Hz, 1H), 3.00 (t, J=4.5 Hz, 1H), 3.54–3.57 (m, 1H),
4.26 (dd, J=10.9, 5.5 Hz, 1H), 4.46 (dd, J=10.9, 3.3 Hz, 1H), 6.65 (d,
J=8.0 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 7.23–7.26 (m, 1H), 7.31 (t,
J=8.0 Hz, 1H), 7.37–7.41 (m, 2H), 8.05 (brs, 1H), 8.33 ppm (d, J=
8.0 Hz, 1H); 13C NMR and DEPT (125 MHz, CDCl3): d=44.86 (CH2),
50.34 (CH), 68.73 (CH2), 101.27 (CH), 104.01 (CH), 109.93 (CH),
112.80 (C), 119.70 (CH), 122.45 (C), 123.16 (CH), 125.07 (CH), 126.55
(CH), 138.67 (C), 140.91 (C), 154.93 ppm (C); IR (ATR): n˜ =3291,
3015, 2925, 2850, 1608, 1586, 1555, 1508, 1473, 1442, 1398, 1337,
1304, 1287, 1262, 1215, 1153, 1133, 1095, 1014, 992, 928, 902, 858,
782, 752, 720, 640 cmÀ1; UV (MeOH): l=224 (sh), 242, 250 (sh), 277
Complex 13: Palladium acetate (131 mg, 0.58 mmol) was added at
room temperature to a solution of the diarylamine 12 (150 mg,
0.557 mmol) in dichloromethane under an argon atmosphere. Pyri-
dine (94 mL, 92.5 mg, 1.17 mmol) was added and the mixture was
stirred at room temperature for 48 h. A 50 mL sample of that solu-
tion was diluted with dichloromethane (1 mL) and analysed by ESI-
MS (Figure 3).
4-Pivaloyloxycarbazole (14): A mixture of diarylamine 12 (100 mg,
0.371 mmol), palladium acetate (12.5 mg, 55.7 mmol) and acetic
acid (5 mL) was placed in a 25 mL round bottom flask. The flask
was sealed with a rubber septum, the septum was fitted with 2
cannulae to allow in/out airflow and the flask was heated at 758C
for 22 h. After cooling to room temperature, the mixture was fil-
tered (Celiteꢄ; ethyl acetate) and the solvent was evaporated. Pu-
rification by column chromatography (silica gel; pentane/ethyl ace-
tate 15:2) provided the carbazole 14 (86.6 mg, 0.324 mmol, 87%)
1
(sh), 285, 319, 331 nm; fluorescence (MeOH): lex =285 nm, lem
=
as colourless solid. M.p. 148–1528C; H NMR (500 MHz, CDCl3): d=
339, 353 nm; MS (EI): m/z (%): 239 (100) [M]+, 183 (46), 182 (31),
154 (76), 128 (13), 127 (17); elemental analysis (%) calcd for
C15H13NO2: C 75.30, H 5.48, N 5.85; found: C 75.51, H 5.60, N 5.85.
1.55 (s, 9H), 6.92 (dd, J=7.9, 0.5 Hz, 1H), 7.16 (d, J=8.1 Hz, 1H),
7.19–7.22 (m, 1H), 7.31–7.34 (m, 2H), 7.37–7.40 (m, 1H), 8.03 (d,
J=7.8 Hz, 1H), 8.13 ppm (brs, 1H); 13C NMR and DEPT (125 MHz,
CDCl3): d=27.49 (3 CH3), 39.45 (C), 107.96 (CH), 110.54 (CH), 112.26
(CH), 115.84 (C), 119.61 (CH), 121.17 (C), 122.19 (CH), 125.84 (CH),
125.96 (CH), 139.30 (C), 141.17 (C), 146.33 (C), 177.01 ppm (C=O);
IR (ATR): n˜ =3530, 2959, 2931, 2887, 2858, 2056, 2030, 1775, 1735,
1701, 1678, 1652, 1459, 1388, 1303, 1235, 1205, 1091, 1017, 988,
958, 869, 885, 836, 806, 776, 717, 648, 621 cmÀ1; UV (MeOH): l=
235, 244 (sh), 256, 280 (sh), 288, 322, 335 nm; fluorescence
(MeOH): lex =288 nm, lem =343, 359 nm; MS (EI): m/z (%): 267 (30)
[M]+, 183 (100), 154 (26), 57 (24); MS (ESI, +25 V): m/z: 268
[M+H]+; MS (ESI, À25 V): m/z: 266 [MÀH]À; elemental analysis (%)
calcd for C17H17NO2: C 76.38, H 6.41, N 5.24; found: C 76.45, H 6.76,
N 5.28.
(À)-(S)-Carazolol (5): A solution of the oxirane 16 (226 mg,
0.945 mmol) and isopropylamine (1.21 mL, 832 mg, 14.1 mmol) in
methanol (3 mL) was stirred at 658C for 2 h. The solvent and
excess isopropylamine were evaporated. Purification of the residue
by column chromatography (silica gel; 100 mL of ethyl acetate
then ethyl acetate/methanol 3:1) afforded after evaporation of the
solvent a colourless solid that was taken up in dichloromethane
and filtered (cotton wool, dichloromethane) to remove silica gel
residues. Evaporation of the solvent provided (À)-(S)-carazolol (5)
(233 mg, 0.781 mmol, 83%) as colourless solid. M.p. 147–1488C;
[a]2D0 =À24.7 (c=1, AcOH) [lit.: [a]D20 =À20.8 (c=1, AcOH)];[8d]
1H NMR (500 MHz, CDCl3): d=1.11 (d, J=6.2 Hz, 3H), 1.12 (d, J=
6.2 Hz, 3H), 2.70 (brs, 2H), 2.88 (spt, J=6.2 Hz, 1H), 2.92 (dd, J=
12.2, 7.3 Hz, 1H), 3.06 (dd, J=12.2, 3.8 Hz, 1H), 4.20–4.33 (m, 3H),
6.67 (d, J=8.0 Hz, 1H), 7.05 (d, 7.9 Hz, 1H), 7.23 (ddd, J=7.9, 6.5,
1.5 Hz, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.36–7.41 (m, 2H), 8.11 (s, 1H),
8.26 ppm (d, J=7.8 Hz, 1H); 13C NMR and DEPT (125 MHz, CDCl3):
d=22.84 (CH3), 23.02 (CH3), 48.99 (CH), 49.45 (CH2), 68.46 (CH),
70.41 (CH2), 101.22 (CH), 103.83 (CH), 110.02 (CH), 112.68 (C), 119.66
(CH), 122.50 (C), 122.91 (CH), 125.01 (CH), 126.69 (CH), 138.69 (C),
140.91 (C), 155.10 ppm (C); IR (ATR): n˜ =3183, 2968, 2922, 2873,
1608, 1586, 1556, 1511, 1442, 1397, 1342, 1303, 1285, 1263, 1215,
1172, 1120, 1102, 1057, 1014, 987, 926, 893, 851, 783, 732, 649,
628 cmÀ1; UV (MeOH): l=223 (sh), 242, 250 (sh), 277 (sh), 285, 319,
332 nm; fluorescence (MeOH): lex =285 nm, lem =339, 354 nm; MS
(EI): m/z (%): 298 (20) [M]+, 183 (100), 154 (19), 72 (46); MS (ESI,
4-Hydroxycarbazole (15): Lithium aluminium hydride (2.4m in THF,
4.0 mL, 9.6 mmol) was added at room temperature to a solution of
carbazolyl pivalate 14 (860 mg, 3.22 mmol) in THF (32 mL) and the
mixture was stirred at this temperature for 15 min. The mixture
was cooled to 08C, water and ethyl acetate were added and the
layers were separated. The aqueous layer was extracted with dieth-
yl ether twice, the combined organic layers were dried (MgSO4)
and the solvent was evaporated. Purification of the residue by
column chromatography (silica gel; pentane/ethyl acetate 5:1) pro-
vided 4-hydroxycarbazole (15) (571 mg, 3.12 mmol, 97%) as colour-
less solid. M.p. 168–1708C (lit.: m.p. 169–1708C);[30] 1H NMR
(500 MHz, CDCl3): d=5.27 (brs, 1H), 6.57 (d, J=7.8 Hz, 1H), 7.02 (d,
J=8.0 Hz, 1H), 7.23–7.27 (m, 2H), 7.38–7.42 (m, 2H), 8.04 (brs, 1H),
8.26 ppm (d, J=7.8 Hz, 1H); 13C NMR and DEPT (125 MHz, CDCl3):
Chem. Eur. J. 2016, 22, 1 – 16
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+10 V): m/z: 299 [M+H]+; HRMS (EI): m/z calcd for C18H22N2O2
V=1734.1(3) ꢂ3, Z=4, 1calcd =1.445 gcmÀ3 m=2.381 mmÀ1
, , l=
+
[M]+: 298.1681; found: 298.1676; elemental analysis (%) calcd for
C18H22N2O2: C 72.46, H 7.43, N 9.39; found: C 72.22, H 7.54, N 9.09.
0.71073 ꢂ, T=198(2) K, q range=3.12–25.408, reflections collected
10296, independent reflections 3152 (Rint =0.0290), 219 parame-
ters. The structure was solved by direct methods and refined by
full-matrix least-squares on F2; final R indices [I> 2s(I)] R1 =0.0306
(+)-(S)-1-Bromo-4-(oxiran-2-ylmethoxy)carbazole (17): A solution
of NBS (115 mg, 0.646 mmol) in acetonitrile (6 mL) was added over
a period of 2 h to a solution of the carbazole 16 (150 mg,
0.627 mmol) and one drop of aqueous hydrobromic acid (48%) in
acetonitrile (6.5 mL). The mixture was stirred at room temperature
under argon for 1.5 h (total reaction time: 3.5 h). The solvent was
removed and the residue was purified by column chromatography
(silica gel; pentane/ethyl acetate 5:1) to provide the bromocarba-
zole 17 (140 mg, 0.440 mmol, 70%) as colourless solid. M.p. 150–
1558C; [a]2D0 = +38.3 (c=0.05, MeOH); 1H NMR (500 MHz, CDCl3):
d=2.89 (dd, J=4.9, 2.6 Hz, 1H), 3.00 (t, J=4.5 Hz, 1H), 3.53–3.56
(m, 1H), 4.21 (dd, J=10.9, 5.6 Hz, 1H), 4.46 (dd, J=10.9, 3.1 Hz,
1H), 6.57 (d, J=8.5 Hz, 1H), 7.27–7.30 (m, 1H), 7.42–7.49 (m, 3H),
8.26 (brs, 1H), 8.31 ppm (d, J=7.8 Hz, 1H); 13C NMR (125 MHz,
CDCl3): d=44.73 (CH2), 50.22 (CH), 69.05 (CH2), 95.77 (C), 102.79
(CH), 110.44 (CH), 113.88 (C), 120.33 (CH), 122.94 (C), 123.45 (CH),
125.75 (CH), 128.16 (CH), 138.22 (C), 139.00 (C), 154.23 ppm (C); IR
(ATR): n˜ =3310, 3064, 3035, 2920, 2843, 1607, 1573, 1504, 1489,
1455, 1405, 1342, 1325, 1289, 1253, 1219, 1154, 1130, 1096, 1020,
994, 978, 927, 901, 878, 856, 788, 760, 744, 728, 624 cmÀ1; UV
(MeOH): l=226 (sh), 244, 254 (sh), 265 (sh), 275, 285, 322, 335 nm;
fluorescence (MeOH): lex =285 nm, lem =350 nm; MS (EI): m/z (%):
319 (99), 317 (100) [M]+, 263 (45), 262 (53), 261 (44), 260 (46), 234
(56), 232 (58), 195 (16), 153 (48), 126 (23); HRMS (EI): m/z calcd for
and wR2 =0.0579; maximal residual electron density 0.265 eꢂÀ3
;
Flack parameter c=À0.008(8). CCDC 1498912 contains the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre.
(À)-(S)-Carvedilol
(6):
2-(2-Methoxyphenoxy)ethan-1-amine
(0.285 mL, 316 mg, 1.89 mmol) was added at room temperature to
a solution of oxirane 16 (226 mg, 0.945 mmol) in isopropanol
(4.5 mL) and the mixture was heated at reflux for 2 h. The mixture
was cooled to room temperature, the solvent was evaporated and
the residue was purified by column chromatography (silica gel;
200 mL of ethyl acetate, then ethyl acetate/methanol 3:1). Evapora-
tion of the solvent provided a residue that was taken up in di-
chloromethane and filtered (cotton wool, dichloromethane) to
remove residual silica gel. Evaporation of the solvent provided (À)-
(S)-carvedilol (6) (292 mg, 0.718 mmol, 76%) as colourless solid.
M.p. 51–548C (lit.: m.p. 121–1238C);[8d] [a]D20 =À17.3 (c=1, AcOH)
[lit.: [a]2D0 =À18.4 (c=1, AcOH)];[8d] 1H NMR (500 MHz, CDCl3): d=
3.01 (dd, J=12.4, 8.0 Hz, 1H), 3.09–3.18 (m, 3H), 3.44 (brs, 2H),
3.80 (s, 3H), 4.15 (t, J=5.1 Hz, 2H), 4.19 (dd, J=9.2, 5.1 Hz, 1H),
4.25–4.33 (m, 2H), 6.64 (d, J=8.0 Hz, 1H), 6.85–6.95 (m, 4H), 7.04
(d, J=8.1 Hz, 1H), 7.17–7.20 (m, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.34–
7.39 (m, 2H), 8.17 (brs, 1H), 8.24 ppm (d, J=7.8 Hz, 1H); 13C NMR
and DEPT (125 MHz, CDCl3): d=48.51 (CH2), 51.84 (CH2), 55.73
(CH3), 68.07 (CH), 68.30 (CH2), 70.10 (CH2), 101.16 (CH), 103.84 (CH),
110.01 (CH), 111.77 (CH), 112.60 (C), 114.16 (CH), 119.65 (CH), 120.92
(CH), 121.75 (CH), 122.42 (C), 122.89 (CH), 124.96 (CH), 126.63 (CH),
138.67 (C), 140.89 (C), 147.93 (C), 149.55 (C), 155.01 ppm (C); IR
(ATR): n˜ =3304, 2927, 2840, 1605, 1588, 1557, 1542, 1502, 1451,
1398, 1334, 1305, 1285, 1251, 1216, 1177, 1122, 1096, 1021, 784,
743, 724 cmÀ1; UV (MeOH): l=223 (sh), 242, 250 (sh), 277 (sh), 285,
319, 332 nm; fluorescence (MeOH): lex =285 nm, lem =339,
354 nm; MS (ESI, +10 V): m/z: 407 [M+H]+.
C15H12BrNO2 [M]+: 317.0051; found: 317.0044; elemental analysis
(%) calcd for C15H12BrNO2: C 56.63, H 3.80, N 4.40; found: C 55.99,
H 3.60, N 4.22.
+
(À)-(S)-1-Bromo-4-(2-hydroxy-3-(isopropylamino)propyloxy)car-
bazole [(À)-(S)-1-bromocarazolol] (18): Isopropylamine (0.20 mL,
0.14 g, 2.4 mmol) was added to a solution of compound 17
(50 mg, 0.16 mmol) in methanol (0.7 mL) and the mixture was
stirred at 658C for 1.5 h. The solvent and excess isopropylamine
were evaporated. Purification of the residue by column chromatog-
raphy (silica gel; 400 mL of pentane/ethyl acetate 1:1, then metha-
nol) afforded (after evaporation of the solvent) a colourless solid
that was taken up in dichloromethane and filtered (cotton wool,
dichloromethane) to remove silica gel residues. Evaporation of the
solvent provided (À)-(S)-1-bromocarazolol (18) (55.1 mg,
0.146 mmol, 91%) as colourless solid. M.p. 153–1548C; [a]2D0 =À6.0
3-(p-Tolylamino)phenyl pivalate (19): A solution of 3-bromophen-
yl pivalate (11) (500 mg, 1.94 mmol) in toluene (6 mL) was added
over a period of 2 h to a refluxing solution of p-toluidine (250 mg,
2.33 mmol), caesium carbonate (760 mg, 2.33 mmol), rac-BINAP
(72.7 mg, 0.117 mmol) and palladium acetate (26.2 mg,
0.117 mmol). The mixture was heated at reflux under argon for
22 h (total reaction time: 24 h). After cooling to room temperature,
the mixture was filtered (Celiteꢄ; ethyl acetate). Evaporation of the
solvent and purification of the residue by column chromatography
(silica gel; petroleum ether/ethyl acetate 20:1) provided diaryl-
amine 19 (452 mg, 1.60 mmol, 82%) as yellow, highly viscous oil.
1H NMR (500 MHz, CDCl3): d=1.34 (s, 9H), 2.31 (s, 3H), 5.67 (brs,
1H), 6.54–6.56 (m, 1H), 6.69 (t, J=2.2 Hz, 1H), 6.80–6.82 (m, 1H),
7.00 (d, J=8.3 Hz, 2H), 7.10 (d, J=8.2 Hz, 2H), 7.20 ppm (t, J=
8.1 Hz, 1H); 13C NMR and DEPT (125 MHz, CDCl3): d=20.69 (CH3),
27.10 (3 CH3), 39.01 (C), 109.31 (CH), 112.79 (CH), 113.59 (CH),
119.52 (2 CH), 129.88 (3 CH), 131.49 (C), 139.51 (C), 145.31 (C),
152.08 (C), 177.02 ppm (C=O); IR (ATR): n˜ =3385, 3028, 2973, 2932,
2869, 1737, 1603, 1513, 1480, 1396, 1363, 1326, 1278, 1240, 1143,
1114, 1030, 998, 963, 902, 813, 761, 684, 617 cmÀ1; UV (MeOH): l=
284 nm; MS (EI): m/z (%): 283 (61) [M]+, 199 (100), 183 (6), 167 (6),
154 (12), 128 (6), 91 (5), 57 (35).
1
(c=0.05, MeOH); H NMR (600 MHz, CDCl3): d=1.11 (d, J=6.2 Hz,
3H), 1.12 (d, J=6.2 Hz, 3H), 2.22 (brs, 2H), 2.85–2.92 (m, 2H), 3.04
(dd, J=12.2, 3.7 Hz, 1H), 4.19–4.23 (m, 2H), 4.25–4.29 (m, 1H), 6.59
(d, J=8.5 Hz, 1H), 7.25–7.28 (m, 1H), 7.41–7.49 (m, 3H), 8.25 (d, J=
7.8 Hz, 1H), 8.28 ppm (brs, 1H). 13C NMR (125 MHz, CDCl3): d=
22.99 (CH3), 23.21 (CH3), 48.94 (CH), 49.38 (CH2), 68.50 (CH), 70.77
(CH2), 95.54 (C), 102.76 (CH), 110.51 (CH), 113.80 (C), 120.30 (CH),
123.01 (C), 123.22 (CH), 125.68 (CH), 128.27 (CH), 138.24 (C), 138.99
(C), 154.48 ppm (C); IR (ATR): n˜ =3300, 3058, 2965, 2923, 2866,
1605, 1573, 1558, 1503, 1453, 1373, 1340, 1324, 1295, 1253, 1219,
1133, 1096, 1021, 988, 882, 785, 731, 634 cmÀ1. UV (MeOH): l=226
(sh), 244, 254 (sh), 265 (sh), 275, 285, 310 (sh), 322, 336 nm; fluores-
cence (MeOH): lex =285 nm, lem =345, 356 nm; MS (EI): m/z (%):
378 (5), 376 (5) [M]+, 263 (34), 261 (35); 154 (5), 116 (9), 72 (100);
MS (ESI, +25 V): m/z: 377, 379 [M+H]+; HRMS (EI): m/z calcd for
C18H21BrN2O2 [M]+: 376.0786; found: 376.0776; elemental analysis
(%) calcd for C18H21BrN2O2: C 57.30, H 5.61, N 7.43; found: C 56.69,
H 5.60, N 7.10.
+
Crystallographic data for compound 18: C18H21BrN2O2, M=
377.28 gmolÀ1, crystal size 0.25ꢅ0.14ꢅ0.12 mm3, orthorhombic,
space group P212121, a=8.044(1) ꢂ, b=11.129(1) ꢂ, c=19.371(3) ꢂ,
3-Methylcarbazol-5-yl pivalate (20): A 10 mL microwave tube was
charged with diarylamine 19 (77.2 mg, 0.272 mmol), palladium ace-
tate (9.2 mg, 41 mmol), cupric acetate (124 mg, 0.681 mmol) and
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acetic acid (1 mL). The tube was irradiated in the microwave reac-
tor at 1308C and 300 W for 3 h. The mixture was cooled to room
temperature, filtered (Celiteꢄ, ethyl acetate) and the solvent was
evaporated. Purification of the crude product by column chroma-
tography (silica gel; petroleum ether/ethyl acetate 20:1) provided
the carbazolyl pivalate 20 (53.3 mg, 0.189 mmol, 69%) as light
(MeOH): lex =287 nm, lem =345, 359 nm; MS (EI): m/z (%): 211 (76)
[M]+, 196 (24), 168 (100), 139 (16), 63 (22); elemental analysis (%)
calcd for C14H13NO: C 79.59, H 6.20, N 6.63; found: C 79.80, H 6.22,
N 6.37.
Crystallographic data for glycoborine (7): C14H13NO, M=
211.25 gmolÀ1, crystal size 0.51ꢅ0.13ꢅ0.08 mm3, monoclinic, space
group P21/n, a=11.474(7) ꢂ, b=5.614(3) ꢂ, c=16.904(11) ꢂ, b=
1
yellow solid. M.p. 1698C; H NMR (500 MHz, CDCl3): d=1.56 (s, 9H),
2.49 (s, 3H), 6.88 (d, J=7.8 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.19–
7.25 (m, 2H), 7.31 (t, J=8.0 Hz, 1H), 7.82 (s, 1H), 8.03 ppm (br s,
1H); 13C NMR and DEPT (125 MHz, CDCl3): d=21.49 (CH3), 27.49 (3
CH3), 39.42 (C), 107.98 (CH), 110.16 (CH), 112.07 (CH), 115.76 (C),
121.33 (C), 122.25 (CH), 125.78 (CH), 127.15 (CH), 128.79 (C), 137.50
(C), 141.47 (C), 146.29 (C), 176.92 ppm (C=O); IR (ATR): n=3344,
2965, 2920, 2855, 1721, 1651, 1611, 1503, 1477, 1396, 1369, 1335,
1308, 1281, 1245, 1209, 1136, 1038, 987, 904, 863, 802, 772, 754,
726, 603 cmÀ1; UV (MeOH): l=238, 248 (sh), 259, 281 (sh), 291,
327, 341 nm; fluorescence (MeOH): lex =291 nm, lem =351,
365 nm; MS (EI): m/z (%): 281 (33) [M]+, 197 (100), 168 (25), 153 (4),
142 (5), 139 (5), 57 (23).
95.720(10)8, V=1083.5(11) ꢂ3, Z=4, 1calcd =1.295 gcmÀ3
,
m=
0.644 mmÀ1, l=1.54178 ꢂ, T=150(2) K, q range=4.46–68.008, re-
flections collected 11632, independent reflections 1948 (Rint
=
0.0375), 148 parameters. The structure was solved by direct meth-
ods and refined by full-matrix least-squares on F2; final R indices
[I> 2s(I)] R1 =0.0422 and wR2 =0.1151; maximal residual electron
density 0.303 eꢂÀ3. CCDC 1500704 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre.
4-Methyl-3-(triisopropylsilyloxy)aniline (23): Chlorotriisopropylsi-
lane (7.2 mL, 6.5 g, 34 mmol) was added to a solution of 2-methyl-
5-nitrophenol (22) (4.00 g, 26.1 mmol) and imidazole (3.56 g,
52.3 mmol) in DMF (50 mL) and the mixture was stirred under
argon at room temperature for 21 h. Water and ethyl acetate were
added and the layers were separated. The organic layer was
washed with sat. aqueous ammonium chloride solution and brine,
dried (MgSO4) and the solvent was evaporated. The crude silyl aryl
ether was taken up in acetic acid (250 mL), placed in a 1 L round
bottom flask and iron powder (14.6 g, 261 mmol) was added. The
flask was fitted to a rotary evaporator and heated for 4 h at 408C
and 600 mbar under continuous rotation. The mixture was filtered
(Celiteꢄ; ethyl acetate) and the solvent was evaporated. The residue
was taken up in ethyl acetate and washed several times with sat.
aqueous potassium carbonate solution until residual acetic acid
had been removed. The solution was dried (MgSO4), the solvent
was evaporated and the residue was purified by column chroma-
tography (silica gel; isohexane/diethyl ether, gradient from 8:1 to
4:1) to provide the aniline 23 (6.60 g, 23.6 mmol, 90%) as red oil.
1H NMR (300 MHz, CDCl3): d=1.11 (d, J=7.0 Hz, 18H), 1.22–1.34
(m, 3H), 2.12 (s, 3H), 3.46 (brs, 2H), 6.17–6.23 (m, 2H), 6.88 (d, J=
7.8 Hz, 1H); MS (EI): m/z (%): 279 (64) [M]+, 236 (100), 208 (37), 194
(19), 180 (24), 166 (21), 106 (17), 90 (20). For further spectroscopic
data see ref. [2b].
5-Hydroxy-3-methylcarbazole (21): Lithium aluminium hydride
(29.4 mg, 0.775 mmol) was added to a solution of carbazolyl piva-
late 20 (54.4 mg, 0.193 mmol) in THF (10 mL) and the mixture was
stirred at room temperature under argon for 45 min. Water and
ethyl acetate were added and the layers were separated. The aque-
ous layer was extracted with ethyl acetate three times and the
combined organic layers were dried (MgSO4). Evaporation of the
solvent and purification of the residue by column chromatography
(silica gel; isohexane/ethyl acetate 6:1) provided the hydroxycarba-
zole 21 (35.0 mg, 0.177 mmol, 92%) as brown solid. M.p. 1308C
(lit.: m.p. 125–1268C);[13b] 1H NMR (500 MHz, CDCl3): d=2.53 (s, 3H),
5.40 (s, 1H), 6.55 (d, J=7.9 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 7.20–
7.23 (m, 2H), 7.28 (d, J=8.2 Hz, 1H), 7.94 (brs, 1H), 8.07 ppm (s,
1H); 13C NMR and DEPT (125 MHz, CDCl3): d=21.43 (CH3), 103.31
(CH), 104.89 (CH), 109.68 (CH), 111.57 (C), 122.42 (C), 122.64 (CH),
126.33 (CH), 126.38 (CH), 128.98 (C), 137.00 (C), 141.67 (C),
151.81 ppm (C); IR (ATR): n˜ =3518, 3416, 3021, 2952, 2921, 2853,
2030, 1710, 1616, 1585, 1507, 1453, 1396, 1339, 1299, 1263, 1214,
1164, 1040, 934, 891, 806, 783, 751, 723, 618 cmÀ1; UV (MeOH): l=
227, 245, 253 (sh), 286, 326, 338 nm; fluorescence (MeOH): lex =
286 nm, lem =348, 361 nm; MS (EI): m/z (%): 197 (100) [M]+, 168
(22), 154 (10), 139 (6), 115 (5), 98 (5), 89 (5), 83 (6).
3-(4-Methyl-3-(triisopropylsilyloxy)phenylamino)phenyl pivalate
Glycoborine (7): Dimethyl sulfate (71 mL, 95 mg, 0.75 mmol) was
added to a solution of hydroxycarbazole 21 (29.7 mg, 0.151 mmol)
and potassium carbonate (41.6 mg, 0.301 mmol) in acetone (4 mL)
under argon and the mixture was heated at reflux for 20 h. After
cooling to room temperature, water and ethyl acetate were added
and the layers were separated. The organic layer was washed with
water twice, dried (MgSO4) and the solvent was evaporated. Purifi-
cation of the residue by column chromatography (silica gel; iso-
hexane/ethyl acetate 15:1) provided glycoborine (7) (28.9 mg,
0.137 mmol, 91%) as a colourless solid. M.p. 1298C (lit.: m.p. 132–
1358C,[12] 133–1348C,[13b] 155–1568C,[10] 154–1568C[13a]). 1H NMR
(500 MHz, CDCl3): d=2.53 (s, 3H), 4.08 (s, 3H), 6.66 (d, J=8.0 Hz,
1H), 7.01 (d, J=8.1 Hz, 1H), 7.20 (dd, J=8.2 Hz, 1.2 Hz, 1H), 7.27
(d, J=8.2 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.92 (brs, 1H), 8.12 ppm
(s, 1H); 13C NMR and DEPT (125 MHz, CDCl3): d=21.44 (CH3), 55.38
(CH3), 100.11 (CH), 103.49 (CH), 109.53 (CH), 112.41 (C), 122.78 (C),
122.90 (CH), 126.17 (CH), 126.43 (CH), 128.87 (C), 136.83 (C), 141.16
(C), 156.20 ppm (C); IR (ATR): n˜ =3400, 3011, 2916, 2848, 2721,
1736, 1624, 1604, 1585, 1554, 1537, 1506, 1487, 1473, 1454, 1438,
1388, 1345, 1313, 1294, 1258, 1225, 1177, 1100, 1058, 973, 916,
879, 801, 781, 745, 716, 699, 653, 620 cmÀ1; UV (MeOH): l=227
(sh), 244, 253 (sh), 278 (sh), 287, 324, 337 nm; fluorescence
(24): A solution of 3-bromophenyl pivalate (11) (350 mg,
1.36 mmol) in toluene (8 mL) was added over a period of 2 h to
a refluxing mixture of the aniline 23 (457 mg, 1.63 mmol), palladi-
um acetate (15.3 mg, 681 mmol), XPhos (64.9 mg, 0.136 mmol) and
caesium carbonate (532 mg, 1.63 mmol) in toluene (7 mL) and the
mixture was heated at reflux for 21 h (total reaction time: 23 h).
The mixture was cooled to room temperature, filtered (Celiteꢄ;
ethyl acetate) and the solvent was evaporated. Purification of the
residue by column chromatography (silica gel; pentane/dichloro-
methane/diethyl ether, gradient from 80:5:1 to 69:5:1) provided di-
arylamine 24 (595 mg, 1.31 mmol, 96%) as light yellow solid. M.p.
1
968C; H NMR (500 MHz, CDCl3): d=1.09 (d, J=7.4 Hz, 18H), 1.22–
1.30 (m, 3H), 1.32 (s, 9H), 2.18 (s, 3H), 5.61 (brs, 1H), 6.52–6.58 (m,
3H), 6.68 (t, J=2.2 Hz, 1H), 6.79 (ddd, J=8.1, 2.1, 0.5 Hz, 1H), 7.01
(d, J=8.0 Hz, 1H), 7.18 ppm (t, J=8.1 Hz, 1H); 13C NMR and DEPT
(125 MHz, CDCl3): d=12.97 (3 CH), 16.43 (CH3), 18.04 (6 CH3), 27.14
(3 CH3), 39.02 (C), 109.23 (CH), 109.42 (CH), 112.07 (CH), 112.86
(CH), 113.72 (CH), 122.41 (C), 129.83 (CH), 131.26 (CH), 140.67 (C),
145.28 (C), 152.13 (C), 154.84 (C), 176.96 ppm (C=O); IR (ATR): n˜ =
3365, 2943, 2866, 1735, 1602, 1515, 1480, 1459, 1409, 1362, 1335,
1275, 1207, 1184, 1140, 1123, 1031, 1005, 908, 880, 861, 841, 805,
775, 756, 682, 645, 625, 605 cmÀ1; UV (MeOH): l=283 nm; MS (EI):
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m/z (%): 455 (100) [M]+, 412 (38), 384 (11), 328 (16), 326 (12), 240
(18), 57 (20); elemental analysis (%) calcd for C27H41NO3Si: C 71.16,
H 9.07, N 3.07; found: C 71.41, H 9.19, N 3.16.
light brown solid. M.p. 958C; H NMR (500 MHz, CDCl3): d=1.16 (d,
J=7.5 Hz, 18H), 1.32–1.42 (m, 3H), 2.41 (s, 3H), 4.06 (s, 3H), 6.64
(d, J=8.0 Hz, 1H), 6.84 (s, 1H), 6.97 (d, J=8.0 Hz, 1H), 7.24 (t, J=
8.0 Hz, 1H), 7.81 (brs, 1H), 8.04 ppm (s, 1H); 13C NMR and DEPT
(125 MHz, CDCl3): d=13.09 (3 CH), 17.53 (CH3), 18.10 (6 CH3), 55.32
(CH3), 99.37 (CH), 100.25 (CH), 103.34 (CH), 112.61 (C), 116.43 (C),
121.38 (C), 124.09 (CH), 125.08 (CH), 138.15 (C), 140.86 (C), 152.83
(C), 155.41 ppm (C); IR (ATR): n˜ =3387, 2944, 2865, 1611, 1589,
1568, 1542, 1508, 1464, 1436, 1396, 1373, 1348, 1325, 1269, 1224,
1166, 1145, 1102, 1066, 1008, 978, 919, 882, 866, 778, 772, 743, 715,
681, 627 cmÀ1; UV (MeOH): l=240, 255 (sh), 263 (sh), 284 (sh), 296,
319, 332 nm; fluorescence (MeOH): lex =296 nm, lem =339,
353 nm; MS (EI): m/z (%): 383 (100) [M]+, 340 (69), 312 (14), 298
(15), 238 (18), 142 (21); elemental analysis (%) calcd for
C23H33NO2Si: C 72.01, H 8.67, N 3.65; found: C 71.68, H 8.51, N 3.64.
3-Methyl-5-pivaloyloxy-2-(triisopropylsilyloxy)carbazole (25):
A
10 mL microwave tube was charged with diarylamine 24 (80.0 mg,
0.176 mmol), palladium acetate (5.9 mg, 26 mmol), cupric acetate
(80.0 mg, 0.440 mmol) and acetic acid (1 mL) and irradiated in the
microwave reactor for 3 h at 300 W and 1308C. The mixture was
cooled to room temperature and filtered (Celiteꢄ; ethyl acetate).
The resulting solution was washed with sat. aqueous potassium
carbonate solution and dried (MgSO4). Evaporation of the solvent
and purification by column chromatography (silica gel; isohexane/
dichloromethane/ethyl acetate 42:5:1) provided pivaloyloxycarba-
zole 25 (65.1 mg, 0.143 mmol, 81%) as colourless solid. M.p. 58–
1
608C; H NMR (500 MHz, CDCl3): d=1.14 (d, J=7.5 Hz, 18H), 1.30–
1.39 (m, 3H), 1.54 (s, 9H), 2.34 (s, 3H), 6.80 (s, 1H), 6.85 (d, J=
7.9 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.74 (s,
1H), 7.91 ppm (brs, 1H); 13C NMR and DEPT (125 MHz, CDCl3): d=
13.08 (3 CH), 17.73 (CH3), 18.09 (6 CH3), 27.50 (3 CH3), 39.39 (C),
99.46 (CH), 107.59 (CH), 112.18 (CH), 114.96 (C), 116.07 (C), 121.50
(C), 123.59 (CH), 124.44 (CH), 138.99 (C), 141.28 (C), 145.52 (C),
153.64 (C), 176.89 ppm (C=O); IR (ATR): n˜ =3386, 2943, 2866, 1734,
1621, 1472, 1445, 1391, 1316, 1231, 1204, 1180, 1119, 1057, 1039,
1011, 920, 879, 831, 746, 719, 680, 606 cmÀ1; UV (MeOH): l=238,
262 (sh), 300, 319, 333 nm; fluorescence (MeOH): lex =300 nm,
lem =342, 357; MS (EI): m/z (%): 453 (100) [M]+, 410 (30), 368 (21),
326 (46), 57 (23); elemental analysis (%) calcd for C27H39NO3Si: C
71.48, H 8.66, N 3.09; found: C 71.64, H 8.95, N 3.35.
Carbalexin A (8): TBAF (1m in THF, 140 mL, 0.140 mmol) was added
to a solution of silyloxycarbazole 27 (36.0 mg, 93.8 mmol) in THF
(3 mL) and the mixture was stirred under argon at room tempera-
ture for 10 min. Water was added and the mixture was extracted
with diethyl ether. The combined organic layers were washed with
water twice and the aqueous layer was extracted with diethyl
ether. The combined organic layers were dried (MgSO4) and the
solvent was evaporated. Purification of the residue by column
chromatography (silica gel; isohexane/ethyl acetate 2:1) provided
carbalexin A (8) (21.3 mg, 93.7 mmol, 100%) as colourless solid.
M.p. 1938C (lit.: m.p. 178–1808C);[14] 1H NMR (500 MHz, CDCl3): d=
2.40 (s, 3H), 4.06 (s, 3H), 4.83 (brs, 1H), 6.65 (d, J=8.0 Hz, 1H),
6.77 (s, 1H), 6.96 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.81
(brs, 1H), 8.01 ppm (s, 1H); 13C NMR and DEPT (125 MHz, CDCl3):
d=16.06 (CH3), 55.36 (CH3), 96.04 (CH), 100.38 (CH), 103.39 (CH),
112.53 (C), 116.20 (C), 116.63 (C), 124.34 (CH), 125.26 (CH), 138.44
(C), 140.85 (C), 152.32 (C), 155.41 ppm (C); IR (ATR): n˜ =3467, 3385,
3071, 2952, 2922, 2826, 1727, 1638, 1606, 1581, 1505, 1464, 1433,
1397, 1350, 1320, 1266, 1213, 1129, 1096, 1060, 1007, 973, 889,
822, 779, 744, 720, 683, 637, 609 cmÀ1; UV (MeOH): l=239, 253
5-Hydroxy-3-methyl-2-(triisopropylsilyloxy)carbazole (26): Lithi-
um aluminium hydride (26.9 mg, 0.708 mmol) was added at room
temperature to
a solution of the carbazole 25 (80.3 mg,
0.177 mmol) in THF (6 mL) and the mixture was stirred under
argon at room temperature for 25 min. Water and ethyl acetate
were added, the layers were separated and the aqueous layer was
extracted with ethyl acetate three times. The combined organic
layers were dried and the solvent was evaporated. Purification of
the residue by column chromatography (silica gel; isohexane/ethyl
acetate 10:1) provided hydroxycarbazole 26 (60.1 mg, 0.163 mmol,
92%) as colourless solid. M.p. 158–1598C; 1H NMR (500 MHz,
CDCl3): d=1.14 (d, J=7.5 Hz, 18H), 1.29–1.40 (m, 3H), 2.39 (s, 3H),
6.53 (d, J=7.8 Hz, 1H), 6.83 (s, 1H), 6.94 (d, J=8.0 Hz, 1H), 7.13 (t,
J=7.9 Hz, 1H), 7.83 (brs, 1H), 7.96 ppm (s, 1H); 13C NMR and DEPT
(125 MHz, CDCl3): d=13.09 (3 CH), 17.54 (CH3), 18.10 (6 CH3), 99.45
(CH), 103.14 (CH), 105.06 (CH), 111.77 (C), 116.00 (C), 121.48 (C),
123.79 (CH), 125.01 (CH), 138.34 (C), 141.42 (C), 150.99 (C),
152.98 ppm (C); IR (ATR): n˜ =3494, 3405, 2945, 2922, 2866, 1725,
1613, 1592, 1508, 1452, 1420, 1393, 1345, 1323, 1275, 1227, 1173,
1126, 1045, 1008, 921, 882, 844, 779, 747, 718, 675, 606 cmÀ1; UV
(MeOH): l=239, 242, 255 (sh), 265 (sh), 284 (sh), 294, 320, 333 nm;
fluorescence (MeOH): lex =294 nm, lem =342, 354 nm; MS (EI): m/z
(%): 369 (100) [M]+, 326 (81), 298 (22), 284 (19), 224 (23), 196 (15),
135 (33), 59 (9).
(sh), 295, 317, 330 nm; fluorescence (MeOH): lex =295 nm, lem
=
336, 351 nm; MS (EI): m/z (%): 227 (100) [M]+, 212 (56), 184 (58),
154 (11), 113 (8); HRMS (EI): m/z calcd for C14H13NO2 [M]+:
+
227.0946; found: 227.0942.
Glybomine A (9): Method A: from carbalexin A (8): Dimethyl sulfate
(66 mL, 88 mg, 0.70 mmol) was added to a mixture of carbalexin A
(8) (31.8 mg, 0.140 mmol), freshly pestled anhydrous potassium
carbonate (38.6 mg, 0.279 mmol) and anhydrous acetone (4.4 mL).
The mixture was heated at reflux under argon for 21 h. After cool-
ing to room temperature, water and ethyl acetate were added and
the layers were separated. The organic layer was washed with
water twice and dried. Evaporation of the solvent and purification
of the residue by column chromatography (silica gel; isohexane/
ethyl acetate 5:1) provided glybomine A (9) (29.0 mg, 0.120 mmol,
86%) as colourless solid. M.p. 179–1818C (lit.: oil);[15] 1H NMR
(500 MHz, [D6]acetone): d=2.31 (s, 3H), 3.88 (s, 3H), 4.04 (s, 3H),
6.66 (d, J=8.0 Hz, 1H), 7.00 (s, 1H), 7.04 (d, J=8.1 Hz, 1H), 7.19 (t,
J=8.0 Hz, 1H), 7.96 (s, 1H), 10.09 ppm (brs, 1H); 13C NMR and
DEPT (125 MHz, [D6]acetone): d=16.87 (CH3), 55.51 (CH3), 55.63
(CH3), 93.02 (CH), 100.53 (CH), 104.50 (CH), 113.17 (C), 116.24 (C),
118.70 (C), 124.57 (CH), 125.60 (CH), 139.88 (C), 142.08 (C), 156.25
(C), 157.43 ppm (C); IR (ATR): n˜ =3412, 3382, 2955, 2922, 2840,
2069, 2023, 2010, 1977, 1887, 1738, 1631, 1609, 1575, 1542, 1505,
1449, 1401, 1378, 1344, 1318, 1272, 1255, 1232, 1197, 1160, 1137,
1096, 1034, 997, 971, 889, 818, 778, 740, 718, 678 cmÀ1; UV
(MeOH): l=239, 264 (sh), 294, 316, 329 nm; fluorescence (MeOH):
lex =294 nm, lem =338, 350 nm; MS (EI): m/z (%): 241 (100) [M]+,
226 (79), 211 (14), 198 (21), 183 (20), 154 (14); elemental analysis
5-Methoxy-3-methyl-2-(triisopropylsilyloxy)carbazole (27): Di-
methyl sulfate (75 mL, 0.10 g, 0.79 mmol) was added to a mixture
of hydroxycarbazole 26 (58.5 mg, 0.158 mmol) and freshly pestled
anhydrous potassium carbonate (43.8 mg, 0.317 mmol) in anhy-
drous acetone (6 mL) and the mixture was heated at reflux under
argon for 20 h. After cooling to room temperature, water was
added and the mixture was extracted with diethyl ether. The com-
bined organic layers were washed with water twice, dried (MgSO4)
and the solvent was evaporated. Purification of the residue by
column chromatography (silica gel; isohexane/ethyl acetate 20:1)
provided methoxycarbazole 27 (54.4 mg, 0.142 mmol, 90%) as
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(%) calcd for C15H15NO2: C 74.67, H 6.27, N 5.81; found: C 74.48, H
6.54, N 5.42.
7.85 ppm (brs, 1H); 13C NMR and DEPT (125 MHz, CDCl3): d=16.89
(CH3), 27.51 (3 CH3), 39.39 (C), 55.35 (CH3), 92.25 (CH), 107.85 (CH),
112.01 (CH), 113,89 (C), 115.96 (C), 119.20 (C), 123.20 (CH), 124.19
(CH), 139.14 (C), 141.04 (C), 145.34 (C), 157.26 (C), 177.05 ppm (C=
O); IR (ATR): n˜ =3399, 2969, 2909, 2869, 1740, 1698, 1621, 1447,
1395, 1364, 1313, 1282, 1229, 1200, 1177, 1120, 1058, 1041, 1002,
941, 898, 864, 821, 769, 745, 720, 675 cmÀ1; UV (MeOH): l=238,
262 (sh), 299, 315, 330 nm; fluorescence (MeOH): lex =299 nm,
lem =355 nm; MS (EI): m/z (%): 311 (49) [M]+, 227 (100), 212 (30),
198 (8), 183 (14), 154 (8), 57 (20); elemental analysis (%) calcd for
C19H21NO3: C 73.29, H 6.80, N 4.50; found: C 73.39, H 6.95, N 4.43.
Compound 32: M.p. 2188C; 1H NMR (500 MHz, CDCl3) d=1.41 (s,
9H), 2.35 (s, 3H), 3.88 (s, 3H), 6.77 (s, 1H), 6.86 (dd, J=8.4, 2.1 Hz,
1H), 7.05 (d, J=1.9 Hz, 1H), 7.70 (s, 1H), 7.85 (d, J=8.3 Hz, 1H),
7.88 ppm (brs, 1H); 13C NMR and DEPT (125 MHz, CDCl3): d=16.68
(CH3), 27.22 (3 CH3), 39.12 (C), 55.50 (CH3), 92.47 (CH), 103.51 (CH),
112.97 (CH), 115.77 (C), 119.46 (C), 119.53 (CH), 121.30 (CH), 121.31
(C), 139.47 (C), 139.60 (C), 148.29 (C), 157.21 (C), 177.70 ppm (C=O);
IR (ATR): n˜ =3424, 3388, 2972, 3939, 2913, 1728, 1635, 1613, 1463,
1449, 1345, 1296, 1228, 1152, 1136, 1036, 1001, 948, 900, 817, 793,
726, 675 cmÀ1; UV (MeOH): l=234, 257 (sh), 302, 328 nm; fluores-
cence (MeOH): lex =302 nm, lem =356 nm; MS (EI): m/z (%): 311
(51) [M]+, 227 (100), 212 (46), 183 (18), 154 (8), 57 (20); elemental
analysis (%) calcd for C19H21NO3: C 73.29, H 6.80, N 4.50; found: C
73.64, H 6.70, N 4.50.
Method B: from carbazole 26: TBAF (1m in THF, 170 mL,
0.170 mmol) was added to a solution of silyloxycarbazole 26
(52.2 mg, 0.141 mmol) in THF (4 mL) and the solution was stirred
for 10 min. Degassed water and ethyl acetate were added, the
layers were separated and the organic layer was washed with de-
gassed water twice. The combined aqueous layers were extracted
with diethyl ether and the combined organic layers were dried
(MgSO4). The solvent was evaporated and the residue was dried in
high vacuum. Without further purification, the dihydroxycarbazole
28 was dissolved in anhydrous acetone (4 mL) and freshly pestled
anhydrous potassium carbonate (58.6 mg, 0.424 mmol) and di-
methyl sulfate (107 mL, 143 mg, 1.13 mmol) were added. The mix-
ture was heated at reflux for 21 h. After cooling to room tempera-
ture, water and ethyl acetate were added and the layers were sep-
arated. The organic layer was washed with water twice, dried
(MgSO4) and the solvent was evaporated. Purification of the resi-
due by column chromatography (silica gel; pentane/ethyl acetate
10:1) provided glybomine A (9) (25.4 mg, 0.105 mmol, 74%) as col-
ourless solid. Spectroscopic data: see above.
3-((3-Methoxy-4-methylphenyl)amino)phenyl pivalate (30): A so-
lution of bromoarene 11 (350 mg, 1.36 mmol) in toluene (8 mL)
was added over a period of 2 h to a refluxing solution of methoxy-
aniline 29 (224 mg, 1.63 mmol), palladium acetate (15.3 mg,
68.1 mmol), XPhos (64.9 mg, 0.136 mmol) and caesium carbonate
(532 mg, 1.63 mmol) in toluene (7 mL) and the mixture was heated
at reflux under argon for 21 h (total reaction time: 23 h). After cool-
ing to room temperature, the solution was filtered (Celiteꢄ; ethyl
acetate). Evaporation of the solvent and purification of the residue
by column chromatography (silica gel; pentane/ethyl acetate 10:1)
provided diarylamine 30 (418 mg, 1.33 mmol, 98%) as yellow oil.
1H NMR (500 MHz, CDCl3): d=1.34 (s, 9H), 2.17 (s, 3H), 3.78 (s, 3H),
5.71 (brs, 1H), 6.55 (ddd, J=8.0, 2.1, 0.7 Hz, 1H), 6.59 (dd, J=7.9,
2.1 Hz, 1H), 6.64 (d, J=2.1 Hz, 1H), 6.74 (t, J=2.2 Hz, 1H), 6.82
(ddd, J=8.2, 2.2, 0.8 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 7.21 ppm (t,
J=8.1 Hz, 1H); 13C NMR and DEPT (125 MHz, CDCl3): d=15.59
(CH3), 27.10 (3 CH3), 39.01 (C), 55.25 (CH3), 102.12 (CH), 109.69 (CH),
111.05 (CH), 112.83 (CH), 113.89 (CH), 120.21 (C), 129.91 (CH),
130.95 (CH), 141.12 (C), 145.13 (C), 152.05 (C), 158.29 (C),
177.00 ppm (C=O); IR (ATR): n˜ =3384, 2970, 2934, 2873, 1739, 1699,
1602, 1557, 1512, 1488, 1479, 1465, 1395, 1365, 1331, 1262, 1209,
5-Hydroxy-2-methoxy-3-methylcarbazole (33): Lithium aluminium
hydride (24.5 mg, 0.646 mmol) was added to a solution of the car-
bazolyl pivalate 31 (50.2 mg, 0.161 mmol) in THF (5 mL) and the
mixture was stirred at room temperature under argon for 30 min.
Water and ethyl acetate were added, and the layers were separat-
ed. The aqueous layer was extracted with ethyl acetate (2ꢅ15 mL),
the combined organic layers were dried (MgSO4) and the solvent
was evaporated. Purification of the residue by column chromatog-
raphy (silica gel; pentane/ethyl acetate 5:2) provided hydroxycar-
bazole 33 (30.1 mg, 0.132 mmol, 82%) as colourless solid. M.p.
2068C; 1H NMR (500 MHz, [D6]acetone): d=2.35 (s, 3H), 3.92 (s,
3H), 6.62 (d, J=7.8 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 7.02 (s, 1H),
7.10 (t, J=7.9 Hz, 1H), 8.04 (s, 1H), 8.80 (s, 1H), 10.01 ppm (brs,
1H); 13C NMR and DEPT (125 MHz, [D6]acetone): d=16.88 (CH3),
55.61 (CH3), 92.97 (CH), 103.07 (CH), 105.03 (CH), 112.67 (C), 116.50
(C), 118.47 (C), 124.56 (CH), 125.51 (CH), 139.92 (C), 142.68 (C),
153.52 (C), 157.29 ppm (C); IR (ATR): n˜ =3390, 3334, 3005, 2943,
2847, 1613, 1508, 1472, 1450, 1394, 1315, 1279, 1225, 1196, 1175,
1160, 1125, 1050, 1022, 995, 957, 894, 824, 781, 743, 718, 671, 648,
608; UV (MeOH): l=239, 263 (sh), 292, 317, 330 nm; fluorescence
(MeOH): lex =292 nm, lem =353 nm; MS (EI): m/z (%): 227 (100)
[M]+, 212 (78), 184 (19), 154 (15), 113 (8); elemental analysis (%)
calcd for C14H13NO2: C 73.99, H 5.77, N 6.16; found: C 73.42, H 5.86,
N 5.94.
1197, 1142, 1113, 1035, 999, 939, 902, 838, 807, 762, 684, 663 cmÀ1
;
UV (MeOH): l=284 nm; MS (EI): m/z (%): 313 (92) [M]+, 229 (100),
57 (33); elemental analysis (%) calcd for C19H23NO3: C 72.82, H 7.40,
N 4.47; found: C 72.57, H 7.38, N 4.65.
2-Methoxy-3-methyl-5-(pivaloyloxy)carbazole (31) and 2-me-
thoxy-3-methyl-7-(pivaloyloxy)carbazole (32): A 10 mL microwave
tube was charged with diarylamine 30 (100 mg, 0.319 mmol), palla-
dium acetate (10.7 mg, 47.7 mmol), cupric acetate (145 mg,
0.798 mmol) and acetic acid (1 mL). The tube was irradiated in the
microwave reactor for 3 h at 300 W and 1308C. The mixture was
cooled to room temperature and filtered (Celiteꢄ; ethyl acetate).
The resulting solution was washed twice with a saturated aqueous
solution of potassium carbonate and dried (MgSO4). Evaporation of
the solvent and purification of the residue by column chromatog-
raphy (silica gel; pentane/ethyl acetate 5:1) provided starting ma-
terial 30 (21 mg, 67 mmol, 21%), the more polar carbazole 32
(13.3 mg, 42.7 mmol, 13%; brown solid) and as most polar com-
pound the carbazole 31 (50.2 mg, 0.161 mmol, 50%; brown solid).
Glybomine A (9): Method C: from hydroxycarbazole 33: Dimethyl
sulfate (51 mL, 68 mg, 0.54 mmol) was added to a mixture of the
hydroxycarbazole 33 (24.5 mg, 0.108 mmol), freshly pestled anhy-
drous potassium carbonate (30 mg, 0.22 mmol) and anhydrous
acetone (5 mL) and the mixture was heated at reflux for 20 h. After
cooling to room temperature, water and ethyl acetate were added
and the layers were separated. The organic layer was washed with
water twice, dried (MgSO4) and the solvent was evaporated. Purifi-
cation of the residue by column chromatography (silica gel; iso-
hexane/ethyl acetate 5:1) provided glybomine A (9) (26.1 mg,
0.108 mmol, 100%) as colourless solid. Spectroscopic data: see
above.
Compound 31: M.p. 1438C; 1H NMR (500 MHz, CDCl3): d=1.55 (s,
9H), 2.31 (s, 3H), 3.83 (s, 3H), 6.64 (s, 1H), 6.85 (d, J=7.7 Hz, 1H),
7.04 (dd, J=8.1, 0.5 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.71 (s, 1H),
Carbazol-4-yl triflate (34): Triethylamine (0.83 mL, 0.60 g,
5.9 mmol) was added at 08C to a solution of 4-hydroxycarbazole
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(15) (1.00 g, 5.46 mmol) in dichloromethane (60 mL) and the mix-
ture was stirred at 08C for 15 min. Trifluoromethanesulfonic anhy-
dride (1.11 mL, 1.86 g, 6.59 mmol) was added slowly and the mix-
ture was stirred at 08C for 1 h. Iced water was added and the mix-
ture was extracted with ethyl acetate. The organic layer was
washed with water and brine and the combined aqueous layers
were extracted with ethyl acetate once. The combined organic
layers were dried (MgSO4) and the solvent was evaporated. Purifi-
cation of the residue by column chromatography provided carba-
zol-4-yl triflate (34) (1.58 g, 5.01 mmol, 92%) as blue solid. M.p. 88–
908C (lit.: m.p. 908C);[31] 1H NMR (500 MHz, CDCl3): d=7.17–7.20
(m, 1H), 7.33 (ddd, J=8.0, 7.0, 1.0 Hz, 1H), 7.39–7.43 (m, 2H), 7.45
(d, J=8.1 Hz, 1H), 7.50 (ddd, J=8.1, 7.1, 1.0 Hz, 1H), 8.26 (brs, 1H),
8.29 ppm (d, J=8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=110.56
(CH), 110.75 (CH), 111.31 (CH), 115.84 (C), 118.74 (q, J=320.7 Hz, C),
119.87 (C), 120.61 (CH), 122.69 (CH), 126.08 (CH), 127.05 (CH),
139.38 (C), 141.32 (C), 144.45 ppm (C); IR (ATR): n˜ =3400, 2030,
1637, 1610, 1573, 1499, 1474, 1456, 1414, 1326, 1288, 1248, 1202,
chloromethane once, the combined organic layers were dried
(MgSO4) and the solvent was evaporated. Purification of the resi-
due by column chromatography (silica gel; pentane/ethyl acetate
10:1) provided bromophenyl pivalate 36 (3.21 g, 11.2 mmol, 98%)
1
as colourless solid. M.p. 558C; H NMR (500 MHz, CDCl3): d=1.35 (s,
9H), 3.79 (s, 3H), 6.82 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H),
7.29 ppm (dd, J=8.8, 2.4 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=
27.13 (3 CH3), 39.06 (C), 56.06 (CH3), 111.96 (C), 113.60 (CH), 126.00
(CH), 129.29 (CH), 140.81 (C), 150.66 (C), 176.28 ppm (C=O); IR
(ATR): n˜ =3008, 2971, 2929, 2836, 1748, 1498, 1469, 1394, 1366,
1300, 1265, 1243, 1199, 1173, 1130, 1111, 1072, 1023, 936, 905, 879,
852, 809, 759,708, 619 cmÀ1; MS (EI): m/z (%): 288 (15), 286 (15)
[M]+, 204 (64), 202 (64), 189 (23), 187 (24), 85 (16), 79 (15), 57
(100), 41 (16); elemental analysis (%) calcd for C12H15BrO3: C 50.19,
H 5.27; found: C 50.48, H 5.43.
2-Methoxy-5-((4-methyl-3-(triisopropylsilyloxy)phenyl)amino)-
phenyl pivalate (37): A solution of bromophenyl pivalate 36
(891 mg, 3.10 mmol) in toluene (15 mL) was added over a period
1181, 1138, 1029, 995, 936, 865, 845, 787, 748, 719, 701, 641 cmÀ1
;
of 2 h to
a refluxing solution of silyloxyaniline 23 (1.04 g,
UV (MeOH): l=213, 234, 243, 256, 281 (sh), 291, 323, 336 nm; fluo-
rescence (MeOH): lex =292 nm, lem =366 nm; MS (EI): m/z (%): 315
(42) [M]+, 182 (80), 154 (100), 128 (16), 127 (19), 77 (10), 69 (10); el-
emental analysis (%) calcd for C13H8F3NO3S: C 49.53, H 2.56, N 4.44,
S 10.17; found: C 49.00, H 2.72, N 4.35, S 9.69.
3.72 mmol), palladium acetate (34.8 mg, 0.155 mmol), XPhos
(148 mg, 0.310 mmol) and caesium carbonate (1.21 g, 3.71 mmol)
in toluene (16 mL) and the mixture was heated at reflux under
argon for 17.5 h (total reaction time: 19.5 h). After cooling to room
temperature, the mixture was filtered (Celiteꢄ; ethyl acetate) and
the solvent was evaporated. Purification of the residue by column
chromatography (silica gel; pentane/ethyl acetate,15:1) provided
diarylamine 37 (1.38 g, 2.84 mmol, 92%) as yellow solid. M.p. 94–
4-(3-Methylbut-2-enyl)carbazole (4-prenylcarbazole) (35): Prenyl
bromide (0.14 mL, 0.18 g, 1.2 mmol) was added to a suspension of
powdered indium (127 mg, 1.11 mmol) in DMF and the mixture
was stirred at room temperature under argon for 2 h. The resulting
solution was added to a mixture of carbazol-4-yl triflate (34)
1
978C; H NMR (500 MHz, CDCl3): d=1.08 (d, J=7.4 Hz, 18H), 1.20–
1.29 (m, 3H), 1.34 (s, 9H), 2.16 (s, 3H), 3.76 (s, 3H), 5.37 (brs, 1H),
6.43 (dd, J=8.0, 2.2 Hz, 1H), 6.47 (d, J=2.2 Hz, 1H), 6.78 (d, J=
2.5 Hz, 1H), 6.82 (dd, J=8.7, 2.5 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H),
6.96 ppm (d, J=8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=12.94 (3
CH), 16.30 (CH3), 18.04 (6 CH3), 27.21 (3 CH3), 39.01 (C), 56.53 (CH3),
107.27 (CH), 110.02 (CH), 113.64 (CH), 113.72 (CH), 116.68 (CH),
120.78 (C), 131.19 (CH), 137.26 (C), 140.83 (C), 142.61 (C), 145.91
(C), 154.84 (C), 176.47 ppm (C=O); IR (ATR): n˜ =3367, 2943, 2866,
1735, 1610, 1578, 1558, 1498, 1464, 1407, 1364, 1339, 1278, 1222,
1184, 1128, 1031, 1003, 921, 881, 857, 797, 758, 675, 640 cmÀ1; UV
(MeOH): l=283 nm; MS (EI): m/z (%): 485 (100) [M]+, 372 (11), 358
(11), 215 (13), 57 (34); elemental analysis (%) calcd for C28H43NO4Si:
C 69.24, H 8.92, N 2.88; found: C 69.49, H 9.04, N 2.83.
(70.0 mg,
0.222 mmol),
tetrakis(triphenylphosphane)palladium
(25.7 mg, 22.2 mmol), lithium chloride (28.2 mg, 0.666 mmol) and
DMF (1 mL) and the mixture was heated at 1008C for 3 h. After
cooling to room temperature, ethyl acetate was added and the
mixture was washed with a saturated aqueous solution of sodium
hydrogen carbonate. The aqueous layer was extracted with ethyl
acetate once, 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
4-prenylcarbazole (35) (32.5 mg, 0.138 mmol, 62%) as light yellow
solid. M.p. 80–838C; 1H NMR (500 MHz, CDCl3): d=1.79 (d, J=
0.9 Hz, 3H), 1.84 (s, 3H), 3.97 (d, J=6.9 Hz, 2H), 5.51–5.55 (m, 1H),
7.06 (d, J=7.2 Hz, 1H), 7.24–7.27 (m, 1H), 7.30 (d, J=7.9 Hz, 1H),
7.34–7.37 (m, 1H), 7.41–7.46 (m, 2H), 8.09 (brs, 1H), 8.16 ppm (d,
J=8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=18.10 (CH3), 25.76
(CH3), 32.83 (CH2), 108.30 (CH), 110.34 (CH), 119.38 (CH), 119.44
(CH), 121.34 (C), 121.86 (CH), 122.92 (CH), 123.41 (C), 125.18 (CH),
125.80 (CH), 133.28 (C), 137.14 (C), 139.46 (C), 139.72 ppm (C); IR
(ATR): n˜ =3400, 3051, 2963, 2910, 1603, 1580, 1504, 1473, 1454,
1435, 1388, 1325, 1294, 1247, 1150, 1115, 1096, 1037, 998, 916, 836,
784, 763, 746, 727 cmÀ1; UV (MeOH): l=238, 247 (sh), 259, 281
6-Methoxy-3-methyl-5-pivaloyloxy-2-(triisopropylsilyloxy)carba-
zole (38) and 6-methoxy-3-methyl-7-pivaloyloxy-2-(triisopropyl-
silyloxy)carbazole (39): Method A: A 10 mL microwave tube was
charged with diarylamine 37 (200 mg, 0.412 mmol), palladium ace-
tate (18.5 mg, 82.4 mmol), cupric acetate (187 mg, 1.03 mmol) and
acetic acid (2 mL). The tube was irradiated in the microwave reac-
tor for 30 min at 1308C and 300 W. The mixture was cooled to
room temperature, transferred to a separatory funnel (diethyl
ether) and washed with a sat. aqueous solution of potassium car-
bonate. The aqueous layer was extracted with diethyl ether once
and the combined organic layers were dried (MgSO4). Evaporation
of the solvent and purification by column chromatography (silica
gel; isohexane/ethyl acetate 10:1) provided the carbazol-5-yl piva-
late 38 (87.2 mg, 0.180 mmol, 44%; light brown solid) and the less
polar carbazol-7-yl pivalate 39 (64.5 mg, 0.133 mmol, 32%; light
brown solid).
(sh), 290, 323, 336 nm; fluorescence (MeOH): lex =290 nm, lem
=
344, 359 nm; MS (EI): m/z (%): 235 (94) [M]+, 220 (100), 205 (33),
204 (30), 191 (20), 180 (40), 167 (41), 102 (10); elemental analysis
(%) calcd for C17H17N: C 86.77, H 7.28, N 5.95; found: C 86.34, H
7.84, N 5.87.
5-Bromo-2-methoxyphenyl pivalate (36): Pivaloyl chloride
(2.1 mL, 2.1 g, 17 mmol) was added to a solution of 5-bromo-2-me-
thoxyphenol (2.32 g, 11.4 mmol), triethylamine (4.7 mL, 3.4 g,
34 mmol) and DMAP (27.9 mg, 0.228 mmol) in dichloromethane
(80 mL) and the solution was stirred at room temperature under
argon for 90 min. The mixture was transferred to a separatory
funnel (dichloromethane) and washed with a sat. aqueous solution
of ammonium chloride. The aqueous layer was extracted with di-
Method B: A 10 mL microwave tube was charged with diarylamine
37 (100 mg, 0.206 mmol), palladium acetate (6.9 mg, 31 mmol)
cupric acetate (93.5 mg, 0.515 mmol) and pivalic acid (0.9 g). The
tube was irradiated in the microwave reactor for 2 h at 1308C and
300 W. The mixture was cooled to room temperature, transferred
to a separatory funnel (diethyl ether) and washed with a sat. aque-
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ous solution of potassium carbonate. The aqueous layer was ex-
tracted with diethyl ether once and the combined organic layers
were dried (MgSO4). Evaporation of the solvent and purification by
column chromatography (silica gel; isohexane/ethyl acetate 10:1)
provided the carbazol-5-yl pivalate 38 (38.0 mg, 78.6 mmol, 38%;
light brown solid) and the less polar carbazol-7-yl pivalate 39
(58.8 mg, 0.122 mmol, 59%; light brown solid).
6-Methoxy-3-methyl-5-(trifluoromethanesulfonyloxy)-2-(triiso-
propylsilyloxy)carbazole (41): Triethylamine (0.29 mL, 0.21 g,
2.1 mmol) was added at 08C to a solution of the hydroxycarbazole
40 (745 mg, 1.86 mmol) in dichloromethane (20 mL) and the mix-
ture was stirred under argon for 5 min. Triflic anhydride (0.38 mL,
631 mg, 2.24 mmol) was added at 08C and the mixture was stirred
at 08C for 10 min. After addition of iced water, the mixture was
transferred to a separatory funnel (dichloromethane). The layers
were separated, the organic layer was washed once with water,
the combined aqueous layers were extracted with dichlorome-
thane and the combined organic layers were dried (MgSO4). Evapo-
ration of the solvent and purification of the residue by column
chromatography (silica gel; isohexane/ethyl acetate 15:2) provided
the carbazolyl triflate 41 (884 mg, 1.66 mmol, 89%) as green-blue
solid. M.p. 119–1208C; 1H NMR (500 MHz, CDCl3): d=1.15 (d, J=
7.5 Hz, 18H), 1.32–1.41 (m, 3H), 2.38 (s, 3H), 3.94 (s, 3H), 6.80 (s,
1H), 7.02 (d, J=8.7 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 7.81 (brs, 1H),
8.00 ppm (s, 1H); 13C NMR (125 MHz, CDCl3): d=13.07 (3 CH), 17.66
(CH3), 18.07 (6 CH3), 57.31 (CH3), 99.34 (CH), 109.65 (CH), 110.44
(CH), 113.69 (C), 117.58 (C), 118.80 (q, J=320.6 Hz, C), 122.29 (C),
123.99 (CH), 132.21 (C), 135.53 (C), 140.29 (C), 144.57 (C),
154.72 ppm (C); IR (ATR): n˜ =3460, 2949, 2868, 1624, 1570, 1558,
1542, 1501, 1464, 1401, 1383, 1327, 1300, 1279, 1234, 1195, 1137,
1094, 1015, 993, 882, 844, 782, 712, 680, 648 cmÀ1; UV (MeOH): l=
218, 242, 266 (sh), 311, 340 nm (sh); fluorescence (MeOH): lex =
311 nm, lem =377 nm; MS (ESI, +10 V): m/z: 532 [M+H]+; MS (ESI,
À50 V): m/z: 530 [MÀH]À; elemental analysis (%) calcd for
C24H32F3NO5SSi: C 54.22, H 6.07, N 2.63, S 6.03; found: C 54.92, H
6.40, N 2.61, S 5.60.
6-Methoxy-3-methyl-5-pivaloyloxy-2-(triisopropylsilyloxy)carbazole
(38): M.p. 105–1088C; 1H NMR (600 MHz, CDCl3): d=1.14 (d, J=
7.5 Hz, 18H), 1.31–1.38 (m, 3H), 1.55 (s, 9H), 2.33 (s, 3H), 3.85 (s,
3H), 6.77 (s, 1H), 6.99 (d, J=8.6 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H),
7.70 (brs, 1H), 7.72 ppm (s, 1H); 13C NMR (150 MHz, CDCl3): d=
13.08 (3 CH), 17.71 (CH3), 18.09 (6 CH3), 27.49 (3 CH3), 39.38 (C),
57.87 (CH3), 99.50 (CH), 107.06 (CH), 111.43 (CH), 115.31 (C), 117.70
(C), 121.16 (C), 123.58 (CH), 134.57 (C), 135.82 (C), 140.10 (C),
144.50 (C), 153.82 (C), 176.32 ppm (C=O); IR (ATR): n˜ =3377, 2943,
2866, 1739, 1699, 1623, 1570, 1558, 1542, 1502, 1463, 1432, 1396,
1331, 1303, 1269, 1231, 1181, 1097, 1042, 1015, 992, 904, 881, 849,
784, 713, 680, 645, 606 cmÀ1; UV (MeOH): l=218, 240, 253 (sh),
267 (sh), 295 (sh), 306, 337 (sh) nm; fluorescence (MeOH): lex =
306 nm, lem =367, 376 nm; MS (EI): m/z (%): 483 (100) [M]+, 440
(10), 399 (58), 356 (25), 324 (12), 57 (36); elemental analysis (%)
calcd for C28H41NO4Si: C 69.52, H 8.54, N 2.90; found: C 69.38, H
8.59, N 2.83.
6-Methoxy-3-methyl-7-pivaloyloxy-2-(triisopropylsilyloxy)carbazole
(39): M.p. 190–1928C; 1H NMR (600 MHz, CDCl3): d=1.15 (d, J=
7.5 Hz, 18H), 1.32–1.38 (m, 3H), 1.41 (s, 9H), 2.38 (s, 3H), 3.89 (s,
3H), 6.80 (s, 1H), 7.01 (s, 1H), 7.44 (s, 1H), 7.68 (brs, 1H), 7.69 ppm
(s, 1H); 13C NMR (150 MHz, CDCl3): d=13.09 (3 CH), 17.58 (CH3),
18.10 (6 CH3), 27.29 (3 CH3), 39.11 (C), 56.85 (CH3), 99.83 (CH),
103.07 (CH), 104.82 (CH), 117.03 (C), 121.08 (C), 121.13 (CH), 121.24
(C), 133.49 (C), 138.58 (C), 139.69 (C), 145.68 (C), 153.35 (C),
177.29 ppm (C=O); IR (ATR): n˜ =3360, 2944, 2864, 1749, 1699, 1641,
1509, 1474, 1429, 1396, 1365, 1278, 1220, 1201, 1180, 1140, 1119,
1020, 1000, 972, 921, 881, 843, 777, 710, 678, 662, 644 cmÀ1; UV
(MeOH): l=216, 233, 263, 312, 332 (sh), 346 (sh) nm; fluorescence
(MeOH): lex =312 nm, lem =371 nm; MS (EI): m/z (%): 483 (100)
[M]+, 399 (53), 324 (14), 57 (32); elemental analysis (%) calcd for
C28H41NO4Si: C 69.52, H 8.54, N 2.90; found: C 69.43, H 8.60, N 2.94.
6-Methoxy-3-methyl-5-(3-methylbut-2-enyl)-2-(triisopropylsilyl-
oxy)carbazole (42): A solution of sodium hydroxide (150 mg,
3.75 mmol) in degassed water (4 mL) was added to a solution of
the carbazolyl triflate 41 (100 mg, 0.188 mmol), 3-methyl-2-butenyl-
boronic acid pinacol ester (83 mL, 73 mg, 0.37 mmol) and tetrakis-
(triphenylphosphane)palladium (21.7 mg, 18.8 mmol) in toluene
(4 mL) and the mixture was stirred under argon at 908C for 21 h.
After cooling to room temperature, the mixture was transferred to
a separatory funnel (diethyl ether) and the aqueous layer was sepa-
rated. The organic layer was washed with water, the combined
aqueous layers were extracted with diethyl ether and the com-
bined organic layers were dried (MgSO4). Evaporation of the sol-
vent and purification of the residue by column chromatography
(silica gel; isohexane/ethyl acetate 10:1 (440 mL) then 5:1) provid-
ed the prenylcarbazole 42 (49.2 mg, 0.109 mmol, 58%) as light
5-Hydroxy-6-methoxy-3-methyl-2-(triisopropylsilyloxy)carbazole
(40): Lithium aluminium hydride (2.4m in THF, 0.80 mL, 1.9 mmol)
was added at 08C to a solution of carbazolyl pivalate 38 (310 mg,
0.641 mmol) in THF (10 mL) and the mixture was stirred at 08C
under argon for 15 min. Water was added and the mixture was ex-
tracted with ethyl acetate four times. The combined organic layers
were dried (MgSO4) and the solvent was evaporated. Purification of
the residue by column chromatography (silica gel; isohexane/ethyl
acetate 5:1) provided the hydroxycarbazole 40 (232 mg,
0.581 mmol, 91%) as colourless solid. M.p. 137–1398C; 1H NMR
(500 MHz, CDCl3): d=1.15 (d, J=7.5 Hz, 18H), 1.31–1.40 (m, 3H),
2.39 (s, 3H), 3.94 (s, 3H), 6.09 (s, 1H), 6.79 (s, 1H), 6.80 (d, J=
8.6 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 7.60 (brs, 1H), 8.01 ppm (s,
1H); 13C NMR (125 MHz, CDCl3): d=13.09 (3 CH), 17.46 (CH3), 18.10
(6 CH3), 57.94 (CH3), 99.34 (CH), 100.50 (CH), 109.94 (CH), 112.09 (C),
116.30 (C), 121.10 (C), 124.19 (CH), 136.29 (C), 139.39 (C), 139.45 (C),
140.65 (C), 153.18 ppm (C); IR (ATR): n˜ =3415, 3362, 2942, 2865,
1622, 1571, 1504, 1463, 1397, 1321, 1274, 1231, 1166, 1138, 1088,
1044, 1014, 988, 881, 845, 780, 711, 675, 653, 606 cmÀ1; UV
(MeOH): l=241, 289 (sh), 299, 338 nm; fluorescence (MeOH): lex =
299 nm, lem =375 nm; MS (EI): m/z (%): 399 (100) [M]+, 356 (37),
324 (32), 150 (28), 142 (23), 134 (11); elemental analysis (%) calcd
for C23H33NO3Si: C 69.13, H 8.32, N 3.51; found: C 69.40, H 8.57, N
3.39.
1
yellow crystals. M.p. 1318C; H NMR (500 MHz, CDCl3): d=1.15 (d,
J=7.5 Hz, 18H), 1.32–1.42 (m, 3H), 1.71 (d, J=0.8 Hz, 3H), 1.94 (s,
3H), 2.38 (s, 3H), 3.87 (s, 3H), 3.93 (d, J=6.4 Hz, 2H), 5.34–5.36 (m,
1H), 6.80 (s, 1H), 6.98 (d, J=8.6 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H),
7.68 (brs, 1H), 7.83 ppm (s, 1H); 13C NMR (125 MHz, CDCl3): d=
13.11 (3 CH), 17.76 (CH3), 18.12 (6 CH3), 18.21 (CH3), 25.66 (CH2),
25.77 (CH3), 57.96 (CH3), 99.35 (CH), 107.55 (CH), 110.76 (CH), 117.31
(C), 120.71 (C), 122.59 (CH), 122.94 (C), 124.23 (CH), 124.29 (C),
132.06 (C), 135.15 (C), 140.33 (C), 150.92 (C), 153.24 ppm (C); IR
(ATR): n˜ =3421, 3031, 2941, 2865, 2724, 1629, 1541, 1459, 1432,
1381, 1303, 1254, 1235, 1178, 1157, 1139, 1085, 1036, 987, 937, 876,
844, 786, 710, 674 cmÀ1; UV (MeOH): l=219, 241, 269 (sh), 298
(sh), 307, 341 nm (sh); fluorescence (MeOH): lex =307 nm, lem
=
370, 381 nm; MS (EI): m/z (%): 451 (100) [M]+, 408 (11), 352 (29),
176 (10); elemental analysis (%) calcd for C28H41NO2Si: C 74.45, H
9.15, N 3.10; found: C 74.26, H 9.21, N 3.07.
Crystallographic data for compound 42: C28H41NO2Si, M=
451.71 gmolÀ1, crystal size 0.24ꢅ0.14ꢅ0.13 mm3, orthorhombic,
space group Pna21, a=23.893(1) ꢂ, b=8.264(1) ꢂ, c=13.438(3) ꢂ,
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V=2653.4(7) ꢂ3, Z=4, 1calcd =1.131 gcmÀ3 m=0.112 mmÀ1
, , l=
A. Jꢁger, A. W. Schmidt, H.-J. Knçlker, J. Org. Chem. 2015, 80, 5666; q) F.
Fumagalli, F. da Silva Emery, Tetrahedron Lett. 2015, 56, 2307; r) C. Schus-
ter, M. Rçnnefahrt, K. K. Julich-Gruner, A. Jꢁger, A. W. Schmidt, H.-J.
Knçlker, Synthesis 2016, 48, 150.
0.71073 ꢂ, T=198(2) K, q range=3.02–25.398, reflections collected
70167, independent reflections 4825 (Rint =0.0421), 303 parame-
ters. The structure was solved by direct methods and refined by
full-matrix least-squares on F2; final R indices [I> 2s(I)] R1 =0.0567
[3] a) T. Watanabe, S. Oishi, N. Fujii, H. Ohno, J. Org. Chem. 2009, 74, 4720;
b) J. J. Neumann, S. Rakshit, T. Drçge, S. Wꢀrtz, F. Glorius, Chem. Eur. J.
2011, 17, 7298; c) L. Ackermann, Chem. Rev. 2011, 111, 1315; d) N. Yoshi-
kai, Y. Wei, Asian J. Org. Chem. 2013, 2, 466.
[4] B. ꢂkermark, L. Eberson, E. Jonsson, E. Pettersson, J. Org. Chem. 1975,
40, 1365.
and wR2 =0.1473; maximal residual electron density 0.522 eꢂÀ3
.
CCDC 1498913 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[5] a) T. Gensch, M. Rçnnefahrt, R. Czerwonka, A. Jꢁger, O. Kataeva, I. Bauer,
H.-J. Knçlker, Chem. Eur. J. 2012, 18, 770; b) T. Gensch, N. Richter, G. The-
umer, O. Kataeva, H.-J. Knçlker, Chem. Eur. J. 2016, 22, 11186.
[6] A. Berndt, M. Gruner, A. W. Schmidt, H.-J. Knçlker, Synlett 2013, 24,
2102.
[7] a) B. Liꢆgault, D. Lee, M. P. Huestis, D. R. Stuart, K. Fagnou, J. Org. Chem.
2008, 73, 5022; b) R. Forke, A. Jꢁger, H.-J. Knçlker, Org. Biomol. Chem.
2008, 6, 2481; c) R. Forke, M. P. Krahl, F. Dꢁbritz, A. Jꢁger, H.-J. Knçlker,
Synlett 2008, 1870.
[8] a) H. Leinert, A. Popelak, W. Bartsch, W. Schaumann, DE 2240599, 1974;
b) D. Sievers, Med. Klin. 1977, 72, 1209; c) W. Bartsch, K. Dietmann, H.
Leinert, G. Sponer, Arzneim.-Forsch. 1977, 27, 1022; d) H. Leinert, DE
3319027, 1984; e) F. Wiedemann, W. Kampe, M. Thiel, G. Sponer, E.
Roesch, K. Dietmann, DE 2815926, 1979; f) F. Hausch, Angew. Chem. Int.
Ed. 2008, 47, 3314; Angew. Chem. 2008, 120, 3360; g) M. A. Soriano-
Ursffla, J. G. Trujillo-Ferrara, J. Correa-Basurto, J. Med. Chem. 2010, 53,
Glybomine B (10): TBAF (1m in THF, 0.71 mL, 0.71 mmol) was
added at 08C to a solution of compound 42 (214 mg, 0.474 mmol)
in THF (15 mL) and the mixture was stirred under argon for 5 min.
Water was added and the mixture was extracted with diethyl ether.
The organic layer was washed with water and the combined aque-
ous layers were extracted with diethyl ether. The combined organic
layers were dried (MgSO4) and the solvent was evaporated. Purifi-
cation of the residue by column chromatography (silica gel; iso-
hexane/ethyl acetate 2:1) provided glybomine B (10) (133 mg,
0.450 mmol, 95%) as colourless solid. M.p. 1688C (lit.: oil);[15]
1H NMR (500 MHz, CDCl3): d=1.70 (d, J=1.2 Hz, 3H), 1.94 (d, J=
0.4 Hz, 3H), 2.40 (s, 3H), 3.88 (s, 3H), 3.92 (d, J=6.4 Hz, 2H), 4.81
(brs, 1H), 5.32–5.34 (m, 1H), 6.79 (s, 1H), 7.00 (d, J=8.6 Hz, 1H),
7.14 (d, J=8.6 Hz, 1H), 7.68 (brs, 1H), 7.82 ppm (s, 1H); 13C NMR
(125 MHz, CDCl3): d=16.32 (CH3), 18.22 (CH3), 25.61 (CH2), 25.76
(CH3), 57.92 (CH3), 96.19 (CH), 107.65 (CH), 110.88 (CH), 115.61 (C),
117.57 (C), 122.46 (CH), 122.84 (C), 124.31 (C), 124.50 (CH), 132.24
(C), 135.11 (C), 140.58 (C), 150.95 (C), 152.73 ppm (C); IR (ATR): n˜ =
3388, 3048, 2972, 2910, 2850, 2827, 1726, 1696, 1626, 1472, 1436,
1399, 1314, 1299, 1250, 1222, 1150, 1127, 1064, 1013, 988, 927,
871, 835, 793, 770, 743, 655, 606 cmÀ1; UV (MeOH): l=217, 241,
266 (sh), 307, 338 (sh) nm; fluorescence (MeOH): lex =307 nm,
lem =379 nm; MS (EI): m/z (%): 295 (100) [M]+, 280 (22), 264 (24),
238 (23), 210 (12), 197 (10); elemental analysis (%) calcd for
C19H21NO2: C 77.26, H 7.17, N 4.74; found: C: 76.94, H 7.33, N 4.67.
´
923; h) M. A. Zielinska-Pisklak, D. M. Pisklak, I. Wawer, Magn. Reson.
Chem. 2011, 49, 284; i) C. Chen-Scarabelli, L. Saravolatz,II, Y. Murad, W.-S.
Shieh, W. Qureshi, J. Di Rezze, R. Abrencillo, T. Gardin, U. Gidwani, L. Sar-
avolatz, G. Faggian, T. Scarabelli, Am. J. Cardiovasc. Drugs 2012, 12, 391;
´
j) M. Ogrodowczyk, K. Dettlaff, A. Jelinska, Mini-Rev. Med. Chem. 2016,
16, 40.
[9] a) T. Walle, J. G. Webb, E. E. Bagwell, U. K. Walle, H. B. Daniell, T. E. Gaff-
ney, Biochem. Pharmacol. 1988, 37, 115; b) W. Bartsch, G. Sponer, K.
Strein, B. Mꢀller-Beckmann, L. Kling, E. Bçhm, U. Martin, H. O. Borbe,
Eur. J. Clin. Pharmacol. 1990, 38, S104; c) R. Mehvar, D. R. Brocks, J.
Pharm. Pharmaceut. Sci. 2001, 4, 185; d) J. Agustian, A. H. Kamaruddin,
S. Bhatia, Process Biochem. 2010, 45, 1587.
[10] A. K. Chakravarty, T. Sarkar, K. Masuda, T. Takey, H. Doi, E. Kotani, K. Shio-
jima, Indian J. Chem. 2001, 40B, 484.
Keywords: alkaloids · catalysis · CÀH bond activation · natural
products · palladium
[11] Nine years earlier, structure 7 had been assigned to a different carba-
zole, glycozolicine. (S. S. Jash, G. K. Biswas, S. K. Bhattacharyya, P. Bhatta-
charyya, A. Chakraborty, B. K. Chowdhury, Phytochemistry 1992, 31,
2503). However, Chakravarty et al. provided evidence that glycozolicine
must have had a different structure (see: Ref. [10]).
[12] S. Cheenpracha, S. Laphookhieo, Phytochem. Lett. 2011, 4, 187.
[13] a) J. T. Kuethe, K. G. Childers, Adv. Synth. Catal. 2008, 350, 1577; b) R.
Bautista, P. Montoya, A. Rebollar, E. BurgueÇo, J. Tamariz, Molecules
2013, 18, 10334; c) H. Gao, Q.-L. Xu, M. Yousufuddin, D. H. Ess, L. Kꢀrti,
Angew. Chem. Int. Ed. 2014, 53, 2701; Angew. Chem. 2014, 126, 2739.
[14] T. Pacher, M. Bacher, O. Hofer, H. Greger, Phytochemistry 2001, 58, 129.
[15] C. Ito, M. Itoigawa, A. Sato, C. M. Hasan, M. A. Rashid, H. Tokuda, T. Mu-
kainaka, H. Nishino, H. Furukawa, J. Nat. Prod. 2004, 67, 1488.
[16] a) M. Schmidt, H.-J. Knçlker, Synlett 2009, 2421; b) M. Rçnnefahrt, PhD
thesis, TU Dresden, 2010.
[1] a) H.-J. Knçlker, K. R. Reddy, Chem. Rev. 2002, 102, 4303; b) H.-J. Knçlker,
Chem. Lett. 2009, 38, 8; c) M. Zhang, Adv. Synth. Catal. 2009, 351, 2243;
d) J. J. Song, J. T. Reeves, D. R. Fandrick, Z. Tan, N. K. Yee, C. H. Sena-
nayake, ARKIVOC 2010, (i), 390; e) I. Bauer, H.-J. Knçlker, Top. Curr. Chem.
2012, 309, 203; f) J. Roy, A. K. Jana, D. Mal, Tetrahedron 2012, 68, 6099;
g) A. W. Schmidt, K. R. Reddy, H.-J. Knçlker, Chem. Rev. 2012, 112, 3193;
h) T. Guo, F. Huang, L. Yu, Z. Yu, Tetrahedron Lett. 2015, 56, 296; i) J.
Yuan, C. Liu, A. Lei, Chem. Commun. 2015, 51, 1394.
[2] a) V. P. Kumar, K. K. Gruner, O. Kataeva, H.-J. Knçlker, Angew. Chem. Int.
Ed. 2013, 52, 11073; Angew. Chem. 2013, 125, 11279; b) R. Hesse, K. K.
Gruner, O. Kataeva, A. W. Schmidt, H.-J. Knçlker, Chem. Eur. J. 2013, 19,
14098; c) C. Thomas, H.-J. Knçlker, Tetrahedron Lett. 2013, 54, 591; d) C.
Bçrger, A. W. Schmidt, H.-J. Knçlker, Org. Biomol. Chem. 2014, 12, 3831;
e) C. Bçrger, A. W. Schmidt, H.-J. Knçlker, Synlett 2014, 25, 1381; f) R.
Hesse, A. Jꢁger, A. W. Schmidt, H.-J. Knçlker, Org. Biomol. Chem. 2014,
12, 3866; g) R. Hesse, O. Kataeva, A. W. Schmidt, H.-J. Knçlker, Chem.
Eur. J. 2014, 20, 9504; h) R. Hesse, M. P. Krahl, A. Jꢁger, O. Kataeva, A. W.
Schmidt, H.-J. Knçlker, Eur. J. Org. Chem. 2014, 4014; i) C. Gassner, R.
Hesse, A. W. Schmidt, H.-J. Knçlker, Org. Biomol. Chem. 2014, 12, 6490;
j) C. Schuster, C. Bçrger, K. K. Julich-Gruner, R. Hesse, A. Jꢁger, G. Kauf-
mann, A. W. Schmidt, H.-J. Knçlker, Eur. J. Org. Chem. 2014, 4741; k) K. K.
Julich-Gruner, O. Kataeva, A. W. Schmidt, H.-J. Knçlker, Chem. Eur. J.
2014, 20, 8536; l) K. K. Julich-Gruner, A. W. Schmidt, H.-J. Knçlker, Syn-
thesis 2014, 46, 2651; m) S. A. Kaliyaperumal, S. Banerjee, U. K. Syam Ku-
mar, Org. Biomol. Chem. 2014, 12, 6105; n) R. Hesse, A. W. Schmidt, H.-J.
Knçlker, Tetrahedron 2015, 71, 3485; o) U. Kober, H.-J. Knçlker, Synlett
2015, 26, 1549; p) C. Schuster, K. K. Julich-Gruner, H. Schnitzler, R. Hesse,
[17] a) M. P. Krahl, A. Jꢁger, T. Krause, H.-J. Knçlker, Org. Biomol. Chem. 2006,
4, 3215; b) R. Forke, M. P. Krahl, T. Krause, G. Schlechtingen, H.-J. Knçlker,
Synlett 2007, 268; c) H.-J. Knçlker, K. R. Reddy, Heterocycles 2003, 60,
1049.
[18] R. J. Steffan, M. A. Ashwell, J. C. Pelletier, W. R. Solvibile, E. M. Matelan,
WO 0206255, 2002.
´
[19] a) G. Wilke, B. Bogdanovic, P. Hardt, P. Heimbach, W. Keim, M. Krçner, W.
Oberkirch, K. Tanaka, E. Steinrꢀcke, D. Walter, H. Zimmermann, Angew.
Chem. Int. Ed. Engl. 1966, 5, 151; Angew. Chem. 1966, 78, 157; b) D. C.
Billington, Chem. Soc. Rev. 1985, 14, 93.
[20] a) H.-J. Knçlker, E. Baum, K. R. Reddy, Tetrahedron Lett. 2000, 41, 1171;
b) R. Czerwonka, K. R. Reddy, E. Baum, H.-J. Knçlker, Chem. Commun.
2006, 711; c) W. Frçhner, K. R. Reddy, H.-J. Knçlker, ARKIVOC 2012, (iii),
330.
[21] a) K. Lee, H. Kim, J. Mo, P. H. Lee, Chem. Asian J. 2011, 6, 2147; b) Q. Dai,
X. Xie, S. Xu, D. Ma, S. Tang, X. She, Org. Lett. 2011, 13, 2302.
&
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www.chemeurj.org
14
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Full Paper
[22] C. Thomas, O. Kataeva, A. W. Schmidt, H.-J. Knçlker, Org. Biomol. Chem.
2014, 12, 872.
[23] W. Kong, C. Fu, S. Ma, Chem. Eur. J. 2011, 17, 13134.
[24] G. M. Sheldrick, SHELXS-97, Programs for Crystal Structure Solution, Uni-
versity of Gçttingen, Germany, 1997.
[25] G. M. Sheldrick, SADABS, v. 2.10, Bruker/Siemens Area Detector Absorp-
tion Correction Program, Bruker AXS Inc., Madison, WI, USA, 2002.
[26] G. M. Sheldrick, SHELXL-97, Programs for Crystal Structure Refinement,
University of Gçttingen, Germany, 1997.
[29] M. Braid, US 3767575, 1973.
[30] J. A. Cummins, M. L. Tomlinson, J. Chem. Soc. 1955, 3475.
[31] J.-M. Ruxer, V. Certal, M. Alasia, L. Bertin, H. Minoux, P. Mailliet, F. Halley,
M. Mendez-Perez, US 0166169, 2011.
[32] Transition Metals in Organic Synthesis, Part 130. For Part 129, see: S. K.
Kutz, A. W. Schmidt, H.-J. Knçlker, Synthesis 2017, 49, DOI: 10.1055/s-
0036-1588322.
[27] L. Farrugia, J. Appl. Crystallogr. 1997, 30, 565.
[28] J.-s. Lee, R. Velarde-Ortiz, A. Guijarro, R. D. Rieke, J. Org. Chem. 2000, 65,
5428.
Received: August 23, 2016
Published online on && &&, 0000
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FULL PAPER
Exploitation: A range of carbazole de-
rivatives with a substituent at the steri-
cally hindered peri-position (C-4 or C-5)
has been synthesised by using a regio-
selective oxidative cyclisation of meta-
oxygen-substituted N-arylanilines. The
oxygen substituent could be exploited
for further functionalisation at this posi-
tion.
&
Alkaloids
C. Brꢀtting, R. Hesse, A. Jꢁger, O. Kataeva,
A. W. Schmidt, H.-J. Knçlker*
&& – &&
Synthesis of Glycoborine, Glybomine
A and B, the Phytoalexin Carbalexin A
and the b-Adrenoreceptor Antagonists
Carazolol and Carvedilol
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ꢃ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!