Total Synthesis of the Natural Carbazoles O -Demethylmurrayanine and Murrastanine A, and of a C4,C4′ Symmetric Murrastanine A Dimer from N -Phenyl-4,5-dimethylene-1,3-oxazolidin-2-one

Article abstract of DOI:10.1055/a-1385-9052

The synthesis of natural carbazoles O -demethylmurrayanine and murrastanine A starting from the title exo -heterocyclic diene- is described. In the synthesis of murrastanine A, its symmetric C4,C4′ dimer can be obtained as the sole product under rather mi

Full text of DOI:10.1055/a-1385-9052

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–K
paper
A
en
J. L. Avila-Melo et al.
Paper
Synthesis
Total Synthesis of the Natural Carbazoles O-Demethylmurrayanine
and Murrastanine A, and of a C4,C4′ Symmetric Murrastanine A
Dimer from N-Phenyl-4,5-dimethylene-1,3-oxazolidin-2-one
José Luis Avila-Melo
Adriana Benavides*
Alfredo Fuentes-Gutiérrez
Joaquín Tamariz
OH
N
H
OMe
murrastanine A
H
N
OMe
H
Hugo A. Jiménez-Vázquez*
0
0
0
0
-0
0
0
1
-
7
5
5
5
-
6
7
9
X
CHO
CHO
O
N
OH
OH
4'
Departamento de Química Orgánica, Escuela Nacional de
Ciencias Biológicas, Instituto Politécnico Nacional, Prol. de
Carpio y Plan de Ayala s/n. Col. Plutarco Elías Calles, Ciudad de
México, CP 11350, México
O
+
4
N
H
OH
N
H
H
hjimenezv@ipn.com
OMe
abenavidesm@ipn.mx
CHO
AHDMeMdeuéprgxaiaoaiClcrnAotoahar,b.jmriCJBemeiPnemesneapn1énvaot1noevin3dezidd5ezvies-0@nVms,QgiáMp@uAznéíqium.pxcutniohiecc.mozomarOsx rgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. de Carpio
y Plan de Ayala s/n. Col. Plutarco Elías Calles, Ciudad de
N
H
OH
O-demethylmurrayanine
Received: 06.12.2020
CHO
CHO
OH
Accepted after revision: 08.02.2021
Published online: 08.02.2021
DOI: 10.1055/a-1385-9052; Art ID: ss-2020-m0625-op
N
H
N
N
H
OMe
H
OH
OMe
1
2
3
Abstract The synthesis of natural carbazoles O-demethylmur-
rayanine and murrastanine A starting from the title exo-heterocyclic
diene is described. In the synthesis of murrastanine A, its symmetric
C4,C4′ dimer can be obtained as the sole product under rather mild
conditions. In all cases, the key intermediate is the same diarylamine.
The carbazole nucleus is obtained through a Pd-promoted cyclization of
the appropriate diarylamine. For the synthesis of O-demethylmur-
rayanine, the cyclization takes place on a silylated derivative. The crystal
structures of murrayanine, two diarylamines, and two non-natural car-
bazole intermediates are also presented.
Figure 1 Murrayanine (1), O-demethylmurrayanine (2), and murra-
stanine A (3)
against human small cell lung cancer, human epidermoid
carcinoma,8 and other cancer cells,7 as well as a strong ac-
tivity against the MCF-7 and SMMC7721 cancer cell lines.12
It has also been found to be weakly active against Staphylo-
coccus aureus and Salmonella typhimurium,9 to have moder-
ate hepatoprotective activity against D-galactosamine-in-
duced cell damage16 and DL-galactosamine-induced toxicity
in WB-F344 cells,15 and potent anti-inflammatory activi-
ty.13 It has even been proposed for the treatment of bron-
chial asthma and chronic obstructive pulmonary disease.20
In contrast, murrastanine A (3) has only been found to be
moderately active against the HL-60 and HeLa cancer cell
lines, at least until now.18
The synthesis of 2 has been reported only once by
Bringmann et al., who synthesized mukonine (4) from 3-
formylindole (5) (Scheme 1a).21 Mukonine was then con-
verted in two steps into murrayanine (1), which was de-
methylated by treatment with BBr3 in CH2Cl2 to afford 2.
Murrastanine A (3) was synthesized by Knölker et al.
through their iron-mediated synthetic methodology
(Scheme 1b), much before it was found in nature.22 In this
case, 3 was obtained through cyclization of the iron com-
plex 6, which in turn was prepared through the electrophilic
Key words O-demethylmurrayanine, murrastanine A, natural carba-
zole synthesis, biscarbazoles, Pd(II)-promoted diarylamine coupling,
exo-heterocyclic dienes, Diels–Alder cycloaddition
The first carbazole found in a living organism, mur-
rayanine [1-methoxy-9H-carbazole-3-carbaldehyde (1)],
was isolated from Murraya koenigii in 1965.1–3 However, the
isolation of its demethylated analogue, O-demethylmur-
rayanine [1-hydroxy-9H-carbazole-3-carbaldehyde (2)],
from Clausena anisata, was not reported until 1989.4 Since
then, 2 has been obtained a number of times from plants of
the Rutaceae family: C. anisata,5 C. excavata,6,7 C. harmandi-
ana,8,9 C. lansium,10–14 C. emarginata,15 and M. koenigii.16,17
On the other hand, murrastanine A [3-hydroxy-1-methoxy-
9H-carbazole (3)] is a carbazole only recently isolated from
M. koenigii18 and also from C. emarginata19 (Figure 1).
Carbazole 2 has been tested for biological activity, ex-
hibiting weak antitumor activity5 and a cytotoxic effect
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. L. Avila-Melo et al.
Paper
Synthesis
CHO
CHO
CO2Me
CHO
OMe
(a)
N
N
H
1
N
H
4
N
H
5
H
OH
OMe
OMe
2
OH
(CO)3Fe
OMe
(b)
(CO)3Fe
BF4
+
H2N
N
H2N
OMe
H
OMe
OMe
3
6
8
7
Scheme 1 (a) Bringmann’s strategy for the synthesis of O-demethylmurrayanine (2); (b) Knölker’s strategy for the synthesis of murrastanine A (3).
substitution reaction on arylamine 7 by the cationic iron
complex 8. So far, no other synthesis of 3 has been reported.
Tamariz and co-workers reported a synthesis of 1-oxy-
genated carbazoles 9, in which one of the key steps was the
palladium-promoted cyclization of diarylamines 10
(Scheme 2). The latter were generated by the hydrolysis of
benzoxazolones 11, which in turn were obtained from the
oxidation of the adducts of the Diels–Alder reaction be-
tween the N-aryl-4,5-dialkylidene-2-oxazolidinones 12
and dienophiles 13.23 By careful selection of the reactants
and slight modifications to the general methodology, a
number of natural and non-natural carbazoles have been
synthesized.24 Other approaches to the synthesis of 1- and
2-oxygenated carbazoles have been developed by the same
research group.25
Herein we report the use of the methodology depicted
in Scheme 2 for the synthesis of compounds 2 and 3, as well
as the unexpected formation of dimer 20. In addition, two
more non-natural carbazoles were obtained along the way.
Carbazole 3 was obtained from murrayanine (1) which,
in turn, was synthesized from diarylamine 14 (Scheme 3).
The latter was not only obtained from the exocyclic diene
12a but was also the key precursor in the synthesis of 2,
through the silyl-protected carbazole 15.
Starting from diene 12a, the key diarylamine 14 was
prepared in 51% overall yield through the series of reactions
reported previously in the synthesis of murrayanine (1,
Scheme 4).26,27 The regioselective Lewis acid catalyzed
Diels–Alder reaction of 12a with acrolein (13a) was carried
out within a short reaction time at low temperature, to
furnish 16 in good yield. Upon aromatization with DDQ,
Z
Z
R'
R
R
CHO
CHO
R'
O
N
O
N
BF3·OEt2
N
H
N
H
9
O
O
+
CH2Cl2
–78 °C, 15 min
89%
OMe
OMe
R'
10
Ph
Ph
12a
13a
16
DDQ, CH2Cl2
60 °C, 12 h
65%
R'
Z
Z
O
N
O
N
+
O
O
CHO
CHO
O
N
NaOH
O
R
R
EtOH/H2O (7:3)
60 °C, 45 min
88%
N
Ph
H
OH
12
13
11
14
17
Scheme 2 Tamariz’s general strategy for the synthesis of carbazoles 9
Scheme 4 Synthesis of diarylamine 14 starting from diene 12a
OH
CHO
CHO
O
O
N
H
N
Ph
N
H
N
H
OH
OMe
OMe
CHO
3
1
14
12a
CHO
N
H
N
H
OH
OTBS
2
15
Scheme 3 General strategy for the synthesis of naturally occurring carbazoles 1–3
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

C
J. L. Avila-Melo et al.
Paper
Synthesis
CHO
Pd(OAc)2
(0.3 equiv)
CHO
CHO
MeI, K2CO3
acetone
60 °C, 45 min
98%
Cu(OAc)2, AcOH
N2, 110–130 °C, 5 d
68%
N
H
N
H
N
H
OMe
OH
OMe
14
18
1
direct method
80%
mCPBA, CH2Cl2
r.t., 20 min
65%
OH
OCHO
K2CO3
EtOH/acetone
r.t., 35 min
85%
N
N
H
OMe
H
OMe
3
19
Scheme 5 Synthesis of murrastanine A (3) from diarylamine 14
followed by basic hydrolysis of the resulting benzoxazol-2-
one 17, the desired diarylamine was obtained as a yellow
solid.
Murrastanine A (3) was synthesized from 14 through
the reaction sequences shown in Scheme 5. The phenolic
hydroxyl group of the latter compound was methylated
with MeI under basic conditions to provide diarylamine 18
in almost quantitative yield. Further cyclization by a Pd(II)-
catalyzed double C–H activation process with Cu(OAc)2 as
the oxidant,28 led to murrayanine (1) in 68% yield.
purification of the carbazole intermediate 19. The isolation
of the final product had to be carried out very carefully
(controlling pH and time) due to the presence of m-chloro-
benzoic acid in the reaction mixture (see experimental sec-
tion).
Carbazole 19 was found to be stable when left in solu-
tion under acidic or neutral conditions after extraction.
However, 3 is not stable in solution under basic or slightly
basic conditions (vide infra), although it can stand longer
1
under neutral or slightly acidic conditions. The H and 13C
The cyclization of 18 was also carried out under stoi-
chiometric conditions [Pd(OAc)2, 1.5 mol equiv], furnishing
1 in lower yield (62%) although in a much shorter reaction
time (6 h) (see experimental section). It should be noted
that the formyl group in 18 (and 1) is very sensitive to the
conditions of the cyclization. In the presence of air, the
formyl group tends to oxidize to the corresponding carbox-
yl, leading to the formation of mukoeic acid and other oxi-
dation by-products, and to lower yields of 1, particularly
when catalytic amounts of Pd(II) are used.
Baeyer–Villiger reaction of 1 afforded the formyl ester
19 in 65% yield, which was hydrolyzed under basic condi-
tions to give 3 in 85% yield. The yield of the Baeyer–Villiger
step was not very good because the ester hydrolyzed slowly
under the reaction conditions. A further improvement to
the overall yield was made by carrying out the transforma-
tion of 1 into 3 in 80% yield, by employing the same re-
agents and similar reaction conditions in each step, without
NMR spectral data of 3 obtained in acetone-d6 correspond-
ed with those reported by Knölker in the first synthesis of
this carbazole.22
The hydrolysis of carbazole 19 to yield 3 also disclosed
an interesting fact. It was observed that murrastanine A (3),
readily observed by TLC, changed into something else in the
reaction mixture, which would become the major product
after longer reaction times (Scheme 6). The 1H and 13C NMR
spectra of this product were consistent with the structure
of a carbazole. A more detailed analysis of the 1H NMR spec-
trum showed that the four signals of ring C were present,
while only a singlet was observed for ring A, suggesting that
the latter had three substituents. As the signals for the O–H,
OMe, and N–H protons were present in the spectrum, the
nature of the third substituent in ring A was not readily ap-
parent. The mass of the molecular ion of this molecule sug-
gested a dimer, a symmetric dimer if both MS and NMR
data were considered.
OCHO
H
N
OMe
K2CO3
NOE
1'
H
2'
N
OH
EtOH/acetone (1:1)
3'
H
OMe
r.t., 150 min
85%
[O]
OH
OH
4'
19
4
1
3
2
CHO
N
H
OMe
H2O2/KHSO4
N
H
3
NOE
MeOH, r.t., 1 h
93%
H
20
OMe
N
H
OMe
1
Scheme 6 Formation of 20 by dimerization of carbazole 3 in the basic hydrolysis of 19 (above); in the oxidation/hydrolysis of 1 through the Dakin
reaction (below).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

D
J. L. Avila-Melo et al.
Paper
Synthesis
Due to the structure of 3, a symmetric dimer in ring A
could be formed only at C2 or C4. The chemical shifts of H2
and H4 in 3 (acetone-d6) are 6.59 and 7.11 ppm, respective-
ly. The chemical shift of the ring-A singlet in the dimer is
6.83 ppm, slightly closer to the chemical shift of H2 in 3,
suggesting the formation of the C4,C4′ dimer 20. Further
confirmation of this assignment came from NOE experi-
ments. Irradiation of the signal attributed to H2 caused an
increase in the intensity of the O–H and OMe signals. Simi-
larly, irradiation of the OMe signal increased the intensity of
the H2 singlet (Scheme 6).
Additional experiments showed that the dimerization
of murrastanine A (3) is spontaneous in solution under ba-
sic conditions and that it is promoted by atmospheric oxy-
gen. A small amount of purified 3 stirred in aqueous etha-
nol under aerobic atmosphere dimerizes, although rather
reluctantly, after a long time. When the hydrolysis of 19
was carried out under nitrogen atmosphere, or when 3 was
left standing in a slightly basic aqueous solution under ni-
trogen, the dimerization took place although slowly. The di-
merization was also slowed if hydroquinone was added to a
slightly basic aqueous solution of 3 under air. An attempt to
obtain murrastanine A (3) by the direct oxidation of 1
through the Dakin reaction,29,30 led to the exclusive forma-
tion of 20 in excellent yield, with no free murrastanine A (3)
being detected (Scheme 6). The above experiments suggest
that the stronger oxidizing conditions (H2O2/H+) in the
Dakin reaction promote dimerization through oxidation of
3, while the dimerization observed in the basic hydrolysis
of 19 takes place through oxidation of the phenolate of 3,
with O2 as the oxidant.
density furnished by the substituents of ring A; the electron
density becomes even higher in the phenolate.
The synthesis of O-demethylmurrayanine (2) started
from diarylamine 14, which was converted into the silylated
derivative 21 in excellent yield by treatment with TBDMSCl
under basic conditions (Scheme 7). The cyclization to car-
bazole 15 was carried out in fair yield with 0.7 equivalent of
Pd(II). A problem with the latter reaction is the partial
deprotection of the phenol, which yielded a mixture of the
expected product 15 and small amounts of 2 and 14. The
cyclization was also carried out with an excess of Pd(II),
with similar results (64% yield, see experimental section).
Thus, this represents an additional example of the use of si-
lylated diarylamines in the synthesis of natural carbazoles
through Pd(II) coupling.54 Desilylation of 15 with TBAF led
1
to 2 in quantitative yield. The H and 13C NMR data (ace-
tone-d6) matched those reported in the literature.21 The di-
rect transformation of 14 into 2 was also attempted, but
only mixtures of products were obtained, with no forma-
tion of the expected carbazole.
CHO
CHO
TBSCl
K2CO3, EtOAc
r.t., 2 h
N
N
H
14
OH
H
21
OTBS
94%
PivOH
115 °C, 12 h
68%
Pd(OAc)2 (0.7 equiv)
CsCO3, AcOH
CHO
CHO
TBAF
EtOAc
r.t., 20 min
98%
N
H
2
N
OH
H
OTBS
15
It is of interest to note that, to date, only one symmetric
C4,C4′ natural carbazole dimer has been reported,31 al-
though a number of symmetric C1,C1′ and a few C2,C2′ bis-
carbazoles have been isolated.32–44 However, we found three
examples of symmetric C4,C4′ bis-carbazoles obtained
through oxidative coupling of the corresponding natural
carbazoles.45–47 It is also remarkable that the oxidative di-
merization of 3 took place under such mild conditions. The
reported synthesis of symmetric carbazole dimers through
oxidative coupling usually occurs under more stringent re-
action conditions.2,48 Typical reagents include manga-
nese(IV) oxide,45 benzoyl peroxide,45 di-tert-butyl perox-
ide,49,50 chloranil,51 iron(III) chloride,40 and iron hexadeca-
fluorophthalocyanine.52 There is one case of formation of
small amounts of a symmetric dimer under Pd-promoted
diarylamine coupling.53 Traces of symmetric dimers have
also been obtained in the reduction of monomers with
LiAlH445 and in oxidations with lead(IV) acetate.46 We found
a single case of efficient formation of a C4,C4′ natural sym-
metric carbazole dimer under mild conditions by oxidative
coupling of the monomer with a vanadium complex.47 The
high reactivity of murrastanine A (3) in the oxidation/di-
merization reaction can be attributed to the high electron
Scheme 7 Conversion of 14 into the natural carbazole O-demethyl-
murrayanine (2)
On a slightly different matter, it was possible to grow
single crystals of diarylamine 14, which led to the determi-
nation of the corresponding X-ray crystal structure (Figure
2a). The two aromatic rings are out of the plane, as evi-
denced by the C4–N1–C7–C8 and C5–C4–N1–C7 dihedral
angles (30.9° and 20.3°, respectively). The nitrogen atom is
planar (the sum of the three associated bond angles is 360°)
with dihedral angles of 30.0° and 15.9° for the H1–N1–C7–
C8 and H1–N1–C4–C5 torsions (H1 on nitrogen), respec-
tively. The plane of the nitrogen is thus more coplanar with
the trisubstituted aromatic ring, as expected from the effect
of the substituents, particularly resonance with the formyl
group; the OH and CHO groups are essentially coplanar
with this ring. The hydroxyl proton is oriented away from
the NH bond to favor the NH···OH hydrogen bond interac-
tion. In addition, the carbonyl oxygen is oriented toward C2.
Likewise, a single crystal of diarylamine 18 was grown
from a mixture of EtOAc, leading to the corresponding X-ray
crystal structure (Figure 2b), which is fairly similar to that
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

E
J. L. Avila-Melo et al.
Paper
Synthesis
of 14 despite the fact that the corresponding space groups
are different (see experimental section). In this case the
C4–N1–C7–C8 and C5–C4–N1–C7 dihedral angles have val-
ues of 25.2° and 20.3°, respectively. The orientation of the
OMe and CHO groups is the same as in 14.
It was also possible to crystallize murrayanine (1). The
X-ray crystal structure is shown in Figure 2c. The asymmet-
ric unit contains two molecules; only one of them is pre-
sented in Figure 2. All the substituent atoms are coplanar
with the heterocycle, with the CHO and OMe groups having
the same orientation as in the corresponding diarylamine.
For carbazole 19, single crystals were grown from mix-
ture of CH2Cl2/hexane (1:1). The corresponding X-ray crys-
tal structure is shown in Figure 2d. In this case the formy-
loxy group at C3 is essentially perpendicular to the plane of
the heterocycle, with a C2–C3–O10–C11 dihedral angle of
96.7° and the carbonyl oxygen oriented toward the ring sys-
tem.
The single-crystal X-ray structure of carbazole 15 is
shown in Figure 2e. The OTBS group is out of the plane of
the fused heterocycle, with a C2–C1–O12–Si13 torsion an-
gle of 37.0°. It is worth noting that even if the orientation of
Figure 2 ORTEP plot of the X-ray crystal structures of (a) 14, (b) 18, (c) 1, (d) 19, and (e) 15. Thermal ellipsoids drawn at 30% probability. For 1, only
one of the two molecules in the asymmetric unit is displayed.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

F
J. L. Avila-Melo et al.
Paper
Synthesis
the OTBS group is not quite coplanar with the plane of the
heterocycle, its orientation and that of the CHO group in the
carbazole is the same as those in diarylamines 14 and 18,
syn with respect to C2.
Table 1 Relative ZPE-Corrected Electronic Energies (ΔE0) and Dipole
Moments () for the syn- and anti-Conformers of Diarylamines 14 and
18, and Carbazoles 1 and 15, Obtained at the B97X-D/aug-cc-pVDZ
Level of Theory
In order to investigate the conformational preference in
the solid state of the formyl group in compounds 1, 14, 15,
and 18, geometry optimizations of both possible orienta-
tions of the formyl group in these molecules (syn and anti
with respect to C2) were carried out with the B97X-D
functional55 combined with the aug-cc-pVDZ basis set56
(see Supporting Information for more details; the B97X-D
functional has demonstrated to be quite good for the calcu-
lation of the relative stability of organic molecules57,58). The
largest difference between the solid-state and the calculat-
ed geometries was observed for the silylated carbazole. The
O–Si bond in the calculated structure was almost perpen-
dicular to the plane of the heterocycle. The Si13–O12–C1–
C2 dihedral angle in the X-ray structure (Figure 2e) was
37.0°, while for the geometry calculated in the gas phase
was 80.6°. The calculations also showed that the syn-con-
former was indeed the most stable in the gas phase for the
four molecules, although only by approximately 1.0
kcal/mol (Table 1). In addition, the dipole moment was
smaller for the syn-conformer by about 1.2 D. Thus, it is
likely that the main reasons for the predominance of the
syn geometry in the solid state are the lower dipole mo-
ment of this conformation and the generation of continu-
ous and compact arrays of chains kept together through hy-
drogen bonding within the crystal structure (Figure 3).
Moleculea
ΔE0 (kcal/mol)
 (D)
14-syn
14-anti
18-syn
18-anti
1-syn
0.00
0.96
0.00
1.23
0.00
1.23
0.00
0.56
3.86
4.69
4.08
5.28
4.07
5.48
4.96
6.16
1-anti
15-syn
15-anti
a The syn- and anti-conformations correspond to the oxygen atom of the C3
formyl group with respect to C2.
which was then transformed into the desired carbazole
through a Baeyer–Villiger/basic hydrolysis reaction se-
quence. In the latter process, the unexpected high-yield ox-
idative dimerization of 3 was observed under rather mild
conditions leading to the symmetric dimer 20. No other ex-
amples of such facile coupling are found in the literature.
Careful manipulation of the dimerization conditions led to
the exclusive formation of either carbazole 3 or dimer 20.
The dimerization took place more efficiently by submitting
1 to the Dakin reaction. Non-natural carbazoles 15 and 19
were also synthesized as intermediates in this work. The X-
ray structures of diarylamines 14 and 18, and of carbazoles
1 and 15 showed that the formyl group adopts the same
conformation (syn with respect to C2) in the four mole-
cules. Additional theoretical calculations indicated that the
syn-conformer is more stable than the anti, probably as a
result of the smaller dipole moment of the former. In the
solid state the syn conformation of the CHO group is further
stabilized by intermolecular hydrogen bonding. Further-
more, to the best of our knowledge, the crystal structure of
1 has been determined for the first time. The crystal struc-
ture of carbazole 19 was also obtained.
Figure 3 Small fragment of the X-ray crystal structure of 15. Hydrogen
bonding between the carbazole N–H bonds and the formyl groups
forms zigzag chains of molecules that extend along one direction within
the crystal lattice. The crystal structures of 1, 14, and 18 bear similar
motifs.
Melting points were determined in a Fisher–Johns apparatus and are
reported uncorrected. TLC was carried out on E. Merck 60F-254 alu-
minum sheets covered with silica gel and visualized with short-wave
UV light or with I2. Column chromatography purification was done
using Natland International Co. silica gel (230–400 or 200–300 mesh).
IR spectra were recorded on a PerkinElmer 200 spectrophotometer.
1H NMR spectra were obtained in 5 mm NMR tubes on 300 (Varian
Mercury), 500 (Varian NMR System), or 600 MHz (Bruker Avance)
spectrometers, using TMS as internal reference in CDCl3, acetone-d6
or CD3OD. 13C NMR spectra were obtained in the same spectrometers
at 75.5, 125.8, or 150.9 MHz, respectively. 1H and 13C NMR spectra
were assigned with the help of additional 2D experiments. High-reso-
lution mass spectra were obtained by electronic impact at 70 eV on a
In summary, the synthetic methodology of Tamariz et
al., which starts from the exo-heterocyclic diene 12a, has
been extended to the total synthesis of the natural carba-
zoles O-demethylmurrayanine (2) and murrastanine A (3)
in fair overall yields. A key intermediate in this work was di-
arylamine 14 from which both carbazoles were obtained. In
the synthesis of 2, silylation of the OH group of 14 allowed
for the Pd-promoted coupling and subsequent deprotection
in good overall yield for the last three steps. In the synthesis
of 3, diarylamine 14 was used to obtain murrayanine (1),
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

G
J. L. Avila-Melo et al.
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Synthesis
JEOL JSM-GCmate II spectrometer. Single crystal X-ray diffraction data
were obtained on an Oxford Diffraction Xcalibur S diffractometer.
Flasks, stirring bars, syringes, and needles employed in anhydrous re-
actions were dried for at least 4 h at 120 °C before use. Solvents were
distilled before use: 1,4-dioxane and THF from Na and benzophenone
ketyl, acetone from KMnO4, CH2Cl2 from NaH, and Et3N from NaOH.
The synthesis of compounds 16, 17, 14, 18, and 1 has been described
previously.26
1-Methoxy-9H-carbazol-3-yl Formate (19)
In a round-bottomed flask provided with a magnetic stir bar, 1 (15.5
mg, 0.07 mmol) and mCPBA (24.15 mg, 0.14 mmol, 2 equiv) were
mixed with CH2Cl2 (2 mL) under N2 atmosphere. The suspension was
stirred at r.t. for 20 min and the solvent evaporated under vacuum.
The residue was purified by column chromatography on silica gel
(hexane/CH2Cl2/EtOAc 50:45:5) to give 19 as a brown oil; yield: 11 mg
(0.045 mmol, 65%); Rf = 0.54 (hexane/EtOAc 7:3); mp 99–100 °C.
IR (CH2Cl2): 3413, 2936, 1738, 1633, 1586, 1505, 1307, 1164 cm–1
.
2,3,4,5,6,7-Hexahydro-2-oxo-3-phenylbenzo[d]oxazole-6-carb-
aldehyde (16)
1H NMR (600 MHz, CDCl3):  = 8.43 (s, 1 H, OCHO), 8.28 (br, 1 H, NH),
7.98 (d, J = 7.8 Hz, 1 H, H-5), 7.45 (t, J = 7.5 Hz, 1 H, H-7), 7.41–7.44 (m,
2 H, H-4, H-8), 7.23 (t, J = 7.30 Hz, 1 H, H-6), 6.70 (d, J = 1.6 Hz, 1 H, H-
2), 3.98 (s, 3 H, OCH3).
13C NMR (150.9 MHZ, CDCl3):  = 160.6 (OCHO), 145.9 (C-1), 143.8 (C-
3), 139.7 (C-8a), 127.9 (C-9a), 126.4 (C-7), 123.7 (C-4b), 123.4 (C-4a),
120.8 (C-5), 119.8 (C-6), 111.4 (C-8), 104.9 (C-4), 100.7 (C-2), 55.6
(OCH3).
Starting from 12a (493 mg, 2.63 mmol), and following the methodol-
ogy already described, afforded 16; yield: 570.4 mg (2.34 mmol, 89%).
Melting point and spectroscopic data matched those reported in the
literature.26
2,3-Dihydro-2-oxo-3-phenylbenzo[d]oxazole-6-carbaldehyde (17)
Starting from 16 (106.0 mg, 0.44 mmol), and following the methodol-
ogy already described afforded 17; yield: 68.0 mg (0.284 mol, 65%).
Melting point and spectroscopic data matched those reported in the
literature.26
HRMS (EI) m/z [M+] calcd for C14H11NO3: 241.0739; found: 241.0749.
3-Hydroxy-1-methoxy-9H-carbazole [murrastanine A (3)]
Method A: In a 5 mL pear-shaped flask provided with a magnetic stir
bar, 1 (27.9 mg, 0.124 mmol) and mCPBA (33.0 mg, 0.191 mmol, 1.54
equiv) were mixed with CH2Cl2 (1.0 mL) under N2 atmosphere, and
the mixture was stirred at r.t. for 20 min. Then 5% aq NaHCO3 (1 mL)
and H2O (10 mL) were added. The mixture was extracted with CH2Cl2
(3 × 10 mL), the combined organic phases were washed with H2O (2 ×
10 mL), dried (anhyd Na2SO4), and the solvent evaporated under vacu-
um. The residue was dissolved in a mixture of EtOH/acetone (1:1, 4
mL) in a 5 mL pear-shaped flask and K2CO3 (36 mg, 0.260 mmol, 2.1
equiv) was added. The suspension was stirred at r.t. for 10 min, treat-
ed with 5% aq HCl (2 mL) down to pH 5. The mixture was extracted
with EtOAc (3 × 10 mL), the combined organic phases dried (anhyd
Na2SO4), and the solvent evaporated under vacuum. The residue was
purified by column chromatography on silica gel (hexane/EtOAc
85:25, then 70:30) to give 3 as a colorless oil; yield: 21 mg (0.099
mmol, 80%).
3-Hydroxy-4-(phenylamino)benzaldehyde (14)
Starting from 17 (152 mg, 0.64 mmol), and following the methodolo-
gy already described afforded 14; yield: 120 mg (0.56 mmol, 88%).
Melting point and spectroscopic data matched those reported in the
literature.26
3-Methoxy-4-(phenylamino)benzaldehyde (18)
Starting from 14 (120 mg, 0.56 mmol), and following the methodolo-
gy already described afforded 18; yield: 125.8 mg (0.55 mmol, 98%).
Melting point and spectroscopic data matched those reported in the
literature.26
1-Methoxy-9H-carbazole-3-carbaldehyde [Murrayanine (1)]
Method A: In a pressure tube provided with a magnetic stir bar, 18
(62.1 mg, 0.22 mmol) and Pd(OAc)2 (75 mg, 0.33 mmol, 1.5 equiv)
were mixed with AcOH (1.0 mL) under N2 atmosphere. The solution
was stirred at 140 °C for 6 h, filtered through a bed of diatomite using
CH2Cl2 to rinse the filter, and washed with sat. aq NaHCO3 (10 mL).
The mixture was extracted with CH2Cl2 (3 × 15 mL), the combined or-
ganic phases were washed with H2O (2 × 15 mL) and dried (anhyd
Na2SO4). The solvent was evaporated under vacuum and the residue
purified by column chromatography on silica gel (hexane/EtOAc 8:2)
to give 1 as a yellowish solid; yield: 38.6 mg (0.17 mmol, 63%).
Method B: In a 5 mL pear-shaped flask provided with a magnetic stir
bar, 19 (12 mg, 0.05 mmol) and K2CO3 (6.95 mg, 0.05 mmol, 1 equiv)
were mixed with a mixture of EtOH/acetone (1:1, 2 mL) under N2 at-
mosphere. The mixture was stirred at r.t. for 35 min, the solvent was
evaporated under vacuum, and the residue treated with 5% aq HCl (1
mL) and H2O (5 mL). The product was extracted with CH2Cl2 (3 × 5
mL), the combined extracts were washed with H2O (2 × 5 mL), dried
(anhyd Na2SO4), and the solvent evaporated under vacuum. The resi-
due was purified by column chromatography on silica gel (hex-
ane/EtOAc 7:3) to give 3 as a colorless oil; yield: 9 mg (0.0425 mmol,
85%); Rf = 0.42 (hexane/EtOAc 6:4).
Method B: In a pressure tube provided with a magnetic stir bar, 18 (9
mg, 0.04 mmol), Pd(OAc)2 (2.7 mg, 0.012 mmol, 0.3 equiv), and
Cu(OAc)2 (18.3 mg, 0.1 mmol, 2.5 equiv) were mixed with AcOH (1.0
mL) under N2 atmosphere. The solution was stirred at 110 °C for 3
days, 120 °C for 2 days, and 130 °C for 24 h, concentrated under vacu-
um and filtered through a bed of diatomite using CH2Cl2 to rinse the
filter. The solvent was evaporated under vacuum and the residue pu-
rified by column chromatography on silica gel (hexane/EtOAc 8:2) to
give 1 as a yellowish solid; yield: 6.1 mg (0.027 mmol, 68%); Rf = 0.41
(hexane/EtOAc 7:3); mp 167–168 °C.
IR (CH2Cl2): 3412, 2927, 2852, 1634, 1591, 1506, 1452, 1317 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.07 (br, 1 H, NH), 7.94 (d, J = 7.8 Hz, 1
H, H-5), 7.41 (dd, J = 7.7, 0.4 Hz, 1 H, H-8), 7.39 (td, J = 6.9, 1.1 Hz, 1 H,
H-7), 7.17 (ddd, J = 7.9, 6.9, 1.2 Hz, 1 H, H-6), 7.07 (d, J = 2.0 Hz, 1 H, H-
4), 6.54 (d, J = 2.0 Hz, 1 H, H-2), 4.75 (s, 1 H, OH), 3.97 (s, 3 H, OCH3).
1H NMR (500 MHz, acetone-d6):  = 10.06 (br, 1 H, NH), 7.96 (br, 1 H,
OH), 7.94 (d, J = 7.7 Hz, 1 H, H-5), 7.50 (d, J = 8.1 Hz, 1 H, H-8), 7.32
(ddd, J = 8.3, 7.2, 1.1 Hz, 1 H, H-7), 7.11 (d, J = 2.1 Hz, 1 H, H-4), 7.06–
7.10 (m, 1 H, H-6), 6.59 (d, J = 2.0 Hz, 1 H, H-2), 3.95 (s, 3 H, OCH3).
Melting point and spectroscopic data agreed with those reported in
the literature.1,26
13C NMR (125.8 MHz, CDCl3):  = 149.9 (C-3), 146.1 (C1), 139.8 (C-8a),
125.7 (C-7), 124.8 (C-4b), 124.0 (C-9a), 123.6 (C-4a), 120.5 (C-5),
119.0 (C-6), 111.0 (C-8), 97.33 (C-4), 97.1 (C-2), 55.6 (OCH3).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

H
J. L. Avila-Melo et al.
Paper
Synthesis
13C NMR (125.8 MHz, acetone-d6):  = 152.3 (C-3), 147.1 (C1), 141.3
(C-8a), 126.0 (C-7), 125.2 (C-9a), 124.8 (C-4b), 124.1 (C-4a), 120.9 (C-
5), 118.4 (C-6), 112.1 (C-8), 98.1 (C-4), 97.4 (C-2), 55.8 (OCH3).
13C NMR (125.8 MHz, CDCl3):  = 190.4 (CHO), 143.2 (C-3), 142.2 (C-
4), 140.2 (C-1′), 129.7 (C-3′), 128.2 (C-1), 127.5 (C-6), 123.8 (C-4′),
121.2 (C-2′), 116.5 (C-2), 111.3 (C-5), 26.0 [C(CH3)3], 18.4 [SiC(CH3)3],
–4.2 [Si(CH3)2].
HRMS (EI) m/z [M+] calcd for C19H25NO2Si: 327.1655; found:
327.1653.
HRMS (EI): m/z [M+] calcd for C13H11NO2: 213.0790; found: 213.0794.
The NMR data determined in acetone-d6 matches that reported by
Knölker.22 The NMR spectra in CDCl3 had not been reported previous-
ly.
1-(tert-Butyldimethylsilyloxy)-9H-carbazole-3-carbaldehyde (15)
Method A: In a high-pressure tube provided with a magnetic stir bar,
21 (25 mg, 0.076 mmol) and Pd(OAc)2 (23.9 mg, 0.106 mmol, 1.4
equiv) were mixed with AcOH (1 mL) under N2 atmosphere. The mix-
ture was stirred at 115 °C for 12 h, filtered through a sintered-glass
Büchner funnel covered with a bed of diatomite, treated with concd
aq NaHCO3 (5 mL), and extracted with EtOAc (3 × 5 mL). The com-
bined organic extracts were was washed with H2O (2 × 5 mL), dried
(anhyd Na2SO4), and concentrated under vacuum. The residue was
purified by column chromatography on silica gel (hexane/EtOAc 95:5)
to give 15 as colorless crystals; yield: 16 mg (0.049 mmol, 64%).
3,3′-Dihydroxy-1,1′-dimethoxy-4,4′-bis-(9,9′H-carbazole) (20)
Method A: In a 10 mL round-bottomed flask provided with a magnetic
stir bar and under N2 atmosphere, 19 (8 mg, 0.033 mmol) and K2CO3
(4.56 mg, 0.033 mmol) were suspended in a mixture of EtOH/acetone
(1:1, 2 mL). The mixture was stirred at r.t. for 2.5 h, and treated with
5% aq HCl (1 mL) and H2O (5 mL). The mixture was extracted with
CH2Cl2 (3 × 5 mL), the combined organic phases were washed with
H2O (2 × 5 mL), and dried (anhyd Na2SO4). The solvent was removed
under vacuum and the residue purified by column chromatography
on silica gel (hexane/EtOAc 7:3) to give 20 as an orange oil; yield: 6
mg (0.014 mmol, 85%); Rf = 0.44 (hexane/EtOAc 1:1).
Method B: In a high-pressure tube provided with a magnetic stir bar,
21 (10 mg, 0.0305 mmol), Pd(OAc)2 (4.8 mg, 0.021 mmol, 0.7 equiv),
Cs2CO3 (3 mg, 0.009 mmol, 0.3 equiv), and PivOH (300 mg, 2.94 mmol,
96.2 equiv) were mixed with AcOH (1 mL). The mixture was stirred
and heated at 120 °C for 36 h. The mixture was filtered through a sin-
tered-glass Büchner funnel covered with a bed of diatomite and con-
centrated under vacuum. The residue was purified by column chro-
matography on silica gel (hexane/EtOAc 95:5) to give 15 as colorless
crystals; yield: 6.8 mg (0.021 mmol, 68%); Rf = 0.83 (hexane/EtOAc
7:3); mp 144 °C.
Method B: In a 50 mL round-bottomed flask provided with a magnetic
stir bar and under N2 atmosphere, 1 (18 mg (0.080 mmol) and KHSO4
(3 mg, 0.020 mmol) were suspended in MeOH (3 mL). To this mixture
was added 30% H2O2 (5 mg, 0.16 mmol). The mixture was stirred for 1
h at r.t.; EtOAc (5 mL) was added and then 5% HCl was added until pH
4 (about 3 mL). The product was extracted with EtOAc (3 × 5 mL), the
combined organic phases were dried (anhyd Na2SO4), and the solvent
removed under vacuum. The residue was purified by column chroma-
tography on silica gel (hexane/EtOAc 7:3) to yield 20 as a dark green
oil;59 yield: 16 mg (0.037 mmol, 93%); Rf = 0.40 (hexane/EtOAc 6:4).
IR (CH2Cl2): 3328, 3928, 2856, 1669, 1600, 1578, 1497, 1342, 1252
cm–1
.
IR (CH2Cl2): 3398, 2925, 2853, 1706, 1625, 1589, 1454, 1313 cm–1
.
1H NMR (500 MHz, CDCl3):  = 10.03 (s, 1 H, CHO), 8.39 (br, 1 H, NH),
8.22 (d, J = 0.6 Hz, 1 H, H-4), 8.11 (d, J = 8.4 Hz, 1 H, H-5), 7.57–7.52
(m, 1 H, H-8), 7.49 (ddd, J = 8.2, 7.1, 1.1 Hz, 1 H, H-7), 7.42 (d, J = 1.3
Hz, 1 H, H-2), 7.29–7.34 (m, 1 H, H-6), 1.09 [s, 9 H, SiC(CH3)3], 0.35 [s,
6 H, Si(CH3)2].
13C NMR (125.8 MHz, CDCl3):  = 191.8 (CHO), 141.6 (C-1), 139.4 (C-
8a), 136.5 (C-9a), 130.2 (C-3), 126.7 (C-7), 124.5 (C-4a), 123.9 (C-4b),
120.8 (C-5), 120.7 (C-6), 119.7 (C-4), 112.35 (C-2), 111.5 (C-8), 25.9
[C(CH3)3], 18.4 [SiC(CH3)3], –4.1 [Si(CH3)2].
1H NMR (300 MHz, CDCl3):  = 8.26 (br, 1 H, NH), 7.38 (d, J = 8.0 Hz, 1
H, H-5), 7.22 (t, J = 7.6 Hz, 1 H, H-7), 6.93 (d, J = 8.0 Hz, 1 H, H-8), 6.87
(s, 1 H, H-2), 6.78 (t, J = 7.4 Hz, 1 H, H-6), 5.07 (s, 1 H, OH), 4.11 (s, 3 H,
OCH3).
1H NMR (500 MHz, acetone-d6):  = 10.18 (br, 1 H, NH), 7.43 (dt, J =
8.1, 0.8 Hz, 1 H, H-5), 7.11 (ddd, J = 8.2, 7.1, 1.2 Hz, 1 H, H-7), 6.98 (s, 1
H, OH), 6.83 (s, 1 H, H-2), 6.75–6.78 (m, 1 H, H-8), 6.58 (ddd, J = 8.0,
7.1, 1.0 Hz, 1 H, H-6), 4.09 (s, 3 H, OCH3).
13C NMR (125.8 MHz, acetone-d6):  = 150.4 (C-3), 147.1 (C-9a), 141.3
(C-8a), 125.6 (C-1), 125.5 (C-7), 124.6 (C-4a), 124.3 (C-4b), 122.4 (C-
8), 118.6 (C-6), 111.6 (C-5), 106.6 (C-4), 98.1 (C-2), 56.0 (OCH3).
HRMS (EI) m/z [M+] calcd for C19H23NO2Si: 325.1498; found:
325.1500.
HRMS (EI) m/z [M+] calcd for C26H20N2O4: 424.1423; found: 424.1419.
1-Hydroxy-9H-carbazole-3-carbaldehyde [O-Demethylmur-
rayanine (2)]
3-(tert-Butyldimethylsilyloxy)-4-phenylaminobenzaldehyde (21)
In a round-bottomed flask provided with a magnetic stir bar, 15 (12
mg, 0.037 mmol) and TBAF (290.2 mg, 1.11 mmol, 30 equiv) were
mixed with EtOAc (1.5 mL) under N2 atmosphere. The mixture was
stirred at r.t. for 20 min, treated with 2% aq HCl (3 mL), and extracted
with EtOAc (3 × 5 mL). The combined organic extracts were washed
with H2O (2 × 10 mL), dried (anhyd Na2SO4), and concentrated under
vacuum. The residue was purified by column chromatography on sili-
ca gel (hexane/EtOAc 7:3), to give 2 as an amorphous white solid;
yield: 7.7 mg (0.036 mmol, 98%); Rf = 0.60 (hexane/EtOAc 6:4); mp
240–241 °C (Lit.4 mp 237–239 °C).
In a 10 mL round-bottom flask, diarylamine 14 (35.8 mg, 0.17 mmol),
TBDMSCl (30.4 mg, 0.20 mmol, 1.18 equiv), and K2CO3 (27.8 mg, 0.20
mmol, 1.18 equiv) were mixed with anhyd EtOAc (2 mL). The mixture
was stirred at r.t. for 2 h, treated with 2% aq HCl (5 mL), and extracted
with EtOAc (3 × 5 mL). The combined organic phases were washed
with H2O (2 × 5 mL), dried (anhyd Na2SO4), and concentrated under
vacuum. The residue was purified by column chromatography on sili-
ca gel (hexane/EtOAc 9:1) to give 21 as a colorless oil; yield: 52 mg
(0.16 mmol, 94%); Rf = 0.48 (hexane/EtOAc 9:1).
IR (CH2Cl2): 3414, 2953, 2930, 2858, 2812, 2723, 1682, 1586, 1525,
IR (CH2Cl2): 3290, 3923, 2852, 1666, 1577, 1454, 1347, 1248, 724 cm–1
.
1280 cm–1
.
1H NMR (500 MHz, acetone-d6):  = 10.80 (br, 1 H, NH), 10.02 (s, 1 H,
CHO), 9.32 (br, 1 H, OH), 8.28 (d, J = 1.1 Hz, 1 H, H-4), 8.21 (d, J = 7.9
Hz, 1 H, H-5), 7.65 (d, J = 8.2 Hz, 1 H, H-8), 7.47 (t, J = 8.2 Hz, 1 H, H-7),
7.44 (d, J = 1.2 Hz, 1 H, H-2), 7.28 (t, J = 7.9 Hz, 1 H , H-6).
1H NMR (500 MHz, CDCl3):  = 9.73 (s, 1 H, CHO), 7.32–7.41 (m, 4 H,
H-2, H-6, H-3′), 7.26 (d, J = 8.2 Hz, 1 H, H-5), 7.22 (d, J = 8.4 Hz, 2 H, H-
2′), 7.10 (t, J = 7.4 Hz, 1 H, H-4′), 6.63 (br, 1 H, NH), 1.05 [s, 9 H,
SiC(CH3)3], 0.32 [s, 6 H, Si(CH3)2].
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

I
J. L. Avila-Melo et al.
Paper
Synthesis
1H NMR (500 MHz, CD3OD):  = 9.91 (s, 1 H, CHO), 8.17 (d, J = 1.3 Hz, 1
H, H-4), 8.10 (d, J = 7.8 Hz, 1 H, H-5), 7.54 (d, J = 8.2 Hz, 1 H, H-8), 7.42
(t, J = 8.2 Hz, 1 H, H-7), 7.34 (d, J = 1.3 Hz, H-2), 7.23 (t, J = 7.5 Hz, 1 H,
H-6).
13C NMR (125.8 MHz, acetone-d6):  = 191.9 (CHO), 144.5 (C-1), 141.4
(C-8a), 134.9 (C-9a), 131.3 (C-3), 127.2 (C-7), 125.1 (C-4a), 124.5 (C-
4b), 121.3 (C-5), 120.8 (C-6), 119.2 (C-4), 112.7 (C-8), 108.4 (C-2).
13C NMR (125.8 MHz, CD3OD):  = 194.1 (CHO), 145.2 (C-1), 141.8 (C-
8a), 136.0 (C-9a), 131.0 (C-3), 127.3 (C-7), 125.4 (C-4a), 124.9 (C-4b),
121.3 (C-5), 121.0 (C-6), 120.2 (C-4), 112.7 (C-8), 108.1 (C-2).
rected for Lorentz and polarization effects. Empirical (multi-scan) ab-
sorption corrections were applied. Structures were solved with
SHELXT60 and refined with SHELXL,61 both within the WinGX62 envi-
ronment. Anisotropic temperature factors were introduced for all
non-hydrogen atoms. Hydrogen atoms were placed in idealized posi-
tions and their atomic coordinates refined using unit weights, except
for hydrogens on oxygen or nitrogen. For the latter, hydrogen atoms
were located from the difference density map and their positions and
isotropic temperature factors were refined accordingly. ORTEP plots
were drawn with PLATON.63 A summary of the crystallographic infor-
mation of these structures is shown in Table 2, including the CCDC
deposition numbers.64
HRMS (EI) m/z [M+] calcd for C13H9NO2: 211.0633; found: 211.0626.
The 13C NMR data in acetone-d6 agrees with that reported in the liter-
ature.21 The 1H NMR data in acetone-d6 and the 1H and 13C NMR data
in CD3OD had not been reported previously.
Theoretical Calculations
Geometries of the syn- and anti-conformers of 1, 14, 15, and 18 were
constructed and visualized with Molden65 and optimized with Gauss-
ian 0966 at the HF/6-31G* level of theory. All optimizations were car-
ried out using the OPT=TIGHT option. The resulting structures were
used as starting points for optimization using the B97X-D function-
al55 combined with the aug-cc-pVDZ basis set.56 Vibrational frequen-
cies of the optimized geometries were calculated at the same level of
theory to verify that they corresponded to minima and to obtain
Gibbs free-energy corrections. All DFT calculations were carried out
with the INT(GRID=ULTRAFINE) option of Gaussian 09.
Single-Crystal X-ray Crystallography
Colorless crystals of 1 and 15 were grown from CH2Cl2, colorless crys-
tals of 19 from CH2Cl2/hexane (1:1). Light yellow crystals of diaryl-
amine 14 were grown from CH2Cl2/hexane (1:1); light ochre crystals
of 18 from EtOAc. Crystallographic measurements were carried out
using an area detector and MoK radiation ( = 0.71073 Å, graphite
monochromator) at r.t. Crystals were mounted in glass fibers. Unit
cell parameters were obtained from least-squares refinement. Data
collection was carried out at 21 °C using  scans. Intensities were cor-
Table 2 Crystal and Structure Refinement Data for Carbazoles 1, 15, 19, and Diarylamines 14 and 18
Structure
1
15
C19H23NO2Si
19
C14H11NO3
14
C13H11NO2
18
C14H13NO2
Empirical formula
Molecular weight
Crystal size (mm)
Crystal system
Space group
C14H11NO2
225.24
325.47
241.24
213.23
227.25
0.11 × 0.19 × 0.52
Orthorhombic
0.16 × 0.27 × 0.46
Monoclinic
0.11 × 0.12 × 0.32
Monoclinic
P 21/c
0.15 × 0.19 × 0.64
Monoclinic
P 21/c
0.47 × 0.49 × 0.75
Orthorhombic
P ca21
P 212121
P 21/c
Unit cell parameters
(Å, °)
a = 6.9111(3),  = 90
b = 8.4474(3),  = 90
c = 39.9853(15),  = 90
a = 8.5223(2),  = 90
a = 10.8851(6),  = 90 a = 11.9372(6),  = 90 a = 20.9024(11),
 = 90
b = 17.5156(3),  =
100.889(2)
b = 14.6132(4),
 = 110.459(7)
b = 7.1152(3),
 = 97.568(4)
b = 7.1900(4),  = 90
c = 12.5874(3),  = 90 c = 7.9560(5),  = 90
c = 12.5195(5),  = 90 c = 7.7353(4),  = 90
Volume (Å3)
2334.38(16)
8
1845.13(7)
4
1185.70(12)
4
1054.09(8)
4
1162.52(11)
4
Z
Density (calcd, Mg/m3)
1.282
0.087
1.172
0.136
1.351
0.096
1.344
0.091
1.298
0.087
Absorption coefficient
(mm–1
)
Theta range (°)
3.157–32.623
24835
2.912–29.523
26941
3.068–32.575
7043
3.283–32.537
11505
3.277–32.540
6828
Reflections collected
Independent reflections 7817
4620
3482
3537
3523
Observed reflections
3622
3648
2095
2840
2823
Final R indices
R1 = 0.0563,
wR2 = 0.1159
R1 = 0.0472,
wR2 = 0.1123
R1 = 0.0508,
wR2 = 0.1200
R1 = 0.0551,
wR2 = 0.1303
R1 = 0.0493,
wR2 = 0.1033
Goodnes-of-fit on F2
1.007
1.025
1.027
1.062
1.065
CCDC deposition number 1998392
1998394
1998396
1998393
1998395
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

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J. L. Avila-Melo et al.
Paper
Synthesis
Conflict of Interest
(15) Xia, H.-M.; Ou Yang, G.-Q.; Li, C.-J.; Yang, J.-Z.; Ma, J.; Zhang, D.;
Li, Y.; Li, L.; Zhang, D.-M. Fitoterapia 2015, 103, 83.
(16) Ma, Q.; Tian, J.; Yang, J.; Wang, A.; Ji, T.; Wang, Y.; Su, Y. Fitotera-
pia 2013, 87, 1.
(17) Tahia, F.; Sikder, M. A. A.; Haque, M. R.; Shilpi, J. A.; Awang, K.; Al
Mansur, M. A.; Rashid, M. A. Dhaka Univ. J. Pharm. Sci. 2015, 14,
29.
(18) Tan, S.-P.; Ali, A. M.; Nafiah, M. A.; Awang, K.; Ahmad, K. Tetra-
hedron 2015, 71, 3946.
(19) Hu, S.; Fu, Y.-H.; Guo, J.-M.; Zhang, W.-H.; Zhang, M.-M.; Liu, Y.-P.
Zhongguo Zhong Yao Za Zhi 2019, 44, 2096.
The authors declare no conflict of interest.
Funding Information
H.A.J.-V. and J.T. thank SIP-IPN for financial support through grants
20151591, 20160567, 20160791, 20171928, 20170902, 20181307,
20180198, 20196462, 20195228, 20202433, and 20200227. J.T. grate-
fully acknowledges CONACYT (grants 178319, A1-S-17131, and
300520) for financial support.Secretaría
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(20) Mukhopadhyay, S.; Chakraborty, M.; Mukherjee, T.;
Bandyopadhyay, A.; Kar, D.; Banerjee, T.; Konar, A.; Jana, D.; Roy,
S.; Bandyopadhyay, S.; Ghosh, B.; Ulaganathan, M.; Johri, R. K.;
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S.; Palakodety, R. K. Patent US 2012/0202868 A1, 2012.
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Synthesis 1998, 1501.
Acknowledgment
We thank Prof. E. Burgueño for his help with HRMS spectra. J.T. and
H.A.J.-V. are fellows of the COFAA-IPN and EDI-IPN fellowship pro-
grams. J.L.A.-M. thanks Fundación Telmex for an undergraduate
scholarship, CONACYT and SIP-IPN for graduate scholarships, and
BEIFI-IPN for complementary stipends.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1385-9052.
S
u
p
p
ortingI
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ortingInformati
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