Palladium mediated intramolecular multiple C-X/C-H cross coupling and C-H activation: Synthesis of carbazole alkaloids calothrixin B and murrayaquinone A

Article abstract of DOI:10.1039/c4ob00493k

Straightforward palladium mediated syntheses of calothrixin B and murrayaquinone A are described. Regioselective palladium mediated intramolecular multiple C-X/C-H cross coupling reaction on N-(4-((2-bromophenyl)amino)-2,5- dimethoxybenzyl)-N-(2-iodophenyl)acetamide followed by CAN oxidation afforded calothrixin B in excellent yield in two steps. A linear synthesis has also been developed for calothrixin B. Utilizing C-H functionalization as well as palladium mediated intramolecular C-X/C-H cross coupling reaction, murrayaquinone A synthesis was achieved. Overall, these synthetic methodologies provide an expedient entry to these biologically active alkaloids in a short reaction sequence. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00493k

Organic &
Biomolecular Chemistry
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Palladium mediated intramolecular multiple
C–X/C–H cross coupling and C–H activation:
synthesis of carbazole alkaloids calothrixin B and
murrayaquinone A†
Cite this: Org. Biomol. Chem., 2014,
12, 6105
Srinivasan A. Kaliyaperumal, Shyamapada Banerjee and Syam Kumar U. K.*
Straightforward palladium mediated syntheses of calothrixin B and murrayaquinone A are described.
Regioselective palladium mediated intramolecular multiple C–X/C–H cross coupling reaction on
N-(4-((2-bromophenyl)amino)-2,5-dimethoxybenzyl)-N-(2-iodophenyl)acetamide followed by CAN oxidation
afforded calothrixin B in excellent yield in two steps. A linear synthesis has also been developed for calo-
thrixin B. Utilizing C–H functionalization as well as palladium mediated intramolecular C–X/C–H cross
coupling reaction, murrayaquinone A synthesis was achieved. Overall, these synthetic methodologies
provide an expedient entry to these biologically active alkaloids in a short reaction sequence.
Received 5th March 2014,
Accepted 9th April 2014
DOI: 10.1039/c4ob00493k
www.rsc.org/obc
Introduction
The pentacyclic carbazole alkaloids calothrixin A (1) and B (2)
were isolated by Rickards et al. from Calothrix cyanobacteria in
1999.1 Calothrixins possess an unprecedented indolo[3,2-j]-
phenanthridine framework with a striking assemblage of quino-
line, quinone and indole pharmacophores. Calothrixin A (1)
and B (2) exhibited antimalarial activity as well as inhibitory
effects on a chloroquine resistant strain of the malarial para-
site Plasmodium falciparum.2 Both 1 and 2 inhibit the growth
of human HeLa cancer cell lines and act as inhibitors of
bacterial-RNA polymerase.3 Kelly et al.4 reported the first total
synthesis of calothrixins in 2000 utilizing an ortho-lithiation
strategy. Several further elegant total syntheses of 1 and 2 were
illustrated in the literature utilizing a hetero Diels–Alder proto-
col,5 Friedel–Crafts reaction,6 palladium mediated tandem
cyclization–cross coupling reaction7 C–H activation,8 FeCl3
mediated domino reaction9 and radical assisted cyclization10
as well as a biomimetic approach.11 Murrayaquinone A (3) is
an indole alkaloid isolated by Furukawa et al. from Murraya
euchrestifolia.12 The plant genus Murraya has been used as a
folk medicine for analgesia and local anesthesia and also for
the treatment of eczema, rheumatism and dropsy (Fig. 1).
Fig. 1 Carbazole alkaloids.
Results and discussion
Multiple Heck reaction of polyhaloarenes provides the oppor-
tunity for building several C–C bonds in a single synthetic
operation,13 however multiple intramolecular C–X/C–H cross
coupling reactions are rarely explored.14 Herein we report the
total synthesis of calothrixin B (2) via multiple as well as step-
wise palladium mediated intramolecular multiple C–X/C–H
cross coupling reactions, and murrayaquinone A (3) synthesis
by C–H activation and also by C–X/C–H cross coupling reaction
from its basic starting materials.
The disconnection strategy for the synthesis of calothrixin
B (2) is depicted in Scheme 1. Calothrixin B (2) could be
obtained by the oxidative demethylation, dehydrogenative oxi-
dation and deacylation of 13. The most salient features of our
Technology Development Centre, Custom Pharmaceutical Services,
Dr Reddy’s Laboratories Ltd, Miyapur, Hyderabad, 500 049, India.
E-mail: syam_kmr@yahoo.com; Fax: +91 4044658699; Tel: +91 4044658618
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00493k
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Scheme 1 Retrosynthetic analogy for calothrixin B.
Scheme 3 Synthesis of carbazole derivatives. Reagents and conditions:
(i) X = H, Pd(OAc)2 (2 equiv.), AcOH, 130 °C, 6 h, 91%; X = Br, Pd(OAc)2,
K2CO3, 10 mol% JohnPhos, 20 mol% PCy3, MeCN, 100 °C, 12 h, 90%.
thesized by the Buchwald–aryl amination protocol. Owing to
the moderate conditions employed in the synthesis of 5b via
Buchwald amination reaction, no C–C bond formation and
dehalogenation were observed.
Initially the synthesis of carbazole 9 was attempted under
intramolecular C–X/C–H cross coupling reaction conditions
from 5b (Scheme 3). To identify the appropriate conditions for
palladium mediated intramolecular C–X/C–H cross coupling
reaction, Pd(OAc)2 was chosen as the catalyst and the reaction
was attempted with various solvent–base combinations in the
Scheme 2 Buchwald–Hartwig amination. Reagents and conditions:
(i) I2, AgNO3, MeOH, r.t., 12 h, 95%; (ii) Pd(dppf)Cl2·CH2Cl2, ( )-BINAP,
Cs2CO3, 8a or 8b, MeCN, 70 °C, 12 h (X = Br, 85%; X = H, 90%).
strategy are the creation of C7a–C7b and C13a–C1a bonds presence of phosphine ligands. The results of these studies are
under palladium mediated intramolecular multiple C–X/C–H summarized in Table 1.
cross coupling reaction in a single synthetic operation from 4.
1,4-Dimethoxy-9H-carbazole-3-carbaldehyde (9) was obtained
The substitution pattern on the A and C rings of 4 would allow in good yield when the reaction was carried out with
the regioselective C–X/C–H cross couplings. The dihaloarene 4 5 mol% of Pd(OAc)2, 20 mol% PCy3 and 10 mol% JohnPhos in
could be accessed via the reductive amination of biaryl- the presence of K2CO3 base in acetonitrile. The reaction was
aminoaldehyde 5 with aniline 10. The iodoaldehyde 6 could be complete after 12 hours at 100 °C (entry 6) and afforded
used as a synthetic precursor for palladium mediated Buch- 9H-carbazole-3-carbaldehyde 9 in 90% yield along with a small
wald aryl amination reaction with 8 to access the biarylamino- percentage (7%) of 5a.
aldehyde 5.
We also extensively studied the C–H activation methodology
The synthesis of the key intermediates 2,5-dimethoxy-4- for the construction of 9 (Table 2) from 5a (Scheme 3). More
(phenylamino)benzaldehyde 5a and 2,5-dimethoxy-4-(2-bromo- importantly, the synthesis of carbazole by C–H activation was
phenylamino)benzaldehyde 5b required for the preparation of carried out in the absence of an oxidizing agent.
calothrixin B (2) is outlined in Scheme 2. The synthesis of 5a
Unreacted starting material 5a was significantly decreased
and 5b were initiated with commercially accessible aldehyde 7. when the C–H activation reactions were performed with
The iodination of aldehyde 7 with a stoichiometric amount of stoichiometric amounts or excess of palladium acetate. Using
iodine in the presence of silver nitrate afforded the iodo alde- 2 equiv. of Pd(OAc)2, the complete consumption of 5a, along
hyde 6 in 95% yield.15 The Buchwald–Hartwig coupling reac- with substantially higher yields of the desired product 9 (more
tion of amine 8b with iodoaldehyde 6 was carried out with than 90%), was achieved within 6 hours when the C–H acti-
Pd(dppf)Cl2·CH2Cl2, rac-BINAP and Cs2CO3 combination in vation reaction was conducted in acetic acid as solvent.
acetonitrile at 60–70 °C for 10–12 hours, and produced 5b in
The direct reductive amination of 9 with 2-iodoaniline (10)
excellent yield. Though the Buchwald aryl amination of 6 with was then carried out with sodium triacetoxyborohydride in the
aryl halo amines is not well exemplified in the literature,16 our presence of TFA in isopropyl acetate solvent17 and afforded 11
attempted aryl amination reaction went very well, notably with in 95% yield (Scheme 4).
less background reaction. Other phosphine ligands such as
The palladium mediated intramolecular C–X/C–H cross
PPFA, PPFE, DPPP, DPPE, PPh3 and P(o-tolyl)3 were employed coupling reaction on 11 under various conditions failed to
in the Buchwald amination, and gave either low conversion or yield to the calothrixin framework probably due to electronic
poor product/reduced substrate ratios. To check the possibility effects. To reduce the electron density and to afford effective
of carbazole synthesis via C–H functionalization, 5a was syn- coordination with Pd(II), N-acylation of 11 was carried out with
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Table 1 Synthesis of carbazole 9 from 5b by C–X/C–H cross coupling reaction
Entry
Catalyst
Solvent
Ligand
X
Time (h)
Yield (%) 5a
Yield (%) 9
1
2
3
4
5
6
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
10 mol% PdCl2
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
Toluene
DMF
DMF
MeCN
MeCN
MeCN
20 mol% PPh3
20 mol% PPh3
20 mol% PPh3
20 mol% PPh3
20 mol% PCy3
20 mol% PCy3 & 10 mol% JohnPhos
Br
Br
Br
Br
Br
Br
12
14
14
16
12
12
0
5
0
0
30
7
0
30
30
20
60
90
Table 2 Synthesis of carbazole 9 from 5a by C–H activation reaction
Entry
Catalyst
Solvent
Ligand
Time (h)
X
Yield (%) 9
1
2
3
4
5
6
7
8
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
10 mol% PdCl2
5 mol% Pd(OAc)2
5 mol% Pd(OAc)2
0.5 equiv. Pd(OAc)2
1 equiv. Pd(OAc)2
2 equiv. Pd(OAc)2
Toluene
DMF
DMF
MeCN
AcOH
AcOH
AcOH
AcOH
20 mol% PPh3
20 mol% PPh3
20 mol% PPh3
20 mol% PPh3
—
—
—
—
24
24
24
24
24
24
10
6
H
H
H
H
H
H
H
H
0
0
0
0
0a
30a
75a
91a
a Reaction was conducted in the absence of ligand and oxidizing agent.
Scheme 4 Iterative synthesis of calothrixin B (2). Reagents and con-
ditions: (i) 2-iodoaniline (10), TFA, NaBH(OAc)3, i-PrOAc, r.t., 10 min,
95%; (ii) NEt3, AcCl, CH2Cl2, 5 °C to r.t., 2 h, 94%; (iii) Pd(OAc)2, K2CO3,
20 mol% PCy3, DMF, 110 °C, 10 h, 90%; (iv) CAN, MeCN–water, r.t., 2 h,
85%.
Scheme 5 Synthesis of calothrixin B (2) by intramolecular multiple
C–X/C–H cross coupling reaction. Reagents and conditions: (i) 2-iodoani-
line (10), TFA, NaBH(OAc)3, i-PrOAc, r.t., 10 min, 95%; (ii) NEt3, AcCl,
CH2Cl2, 5 °C to r.t., 2 h, 94%; (iii) Pd(OAc)2, K2CO3, 10 mol% JohnPhos,
30 mol% PCy3, DMF, 110 °C, 10 h, 88%; (iv) CAN, MeCN–water, r.t.,
2 h, 85%.
acetyl chloride in the presence of triethylamine in dichloro-
methane to afford 12. Subsequently 12 was subjected to the
intramolecular reaction using 5 mol% of Pd(OAc)2, 20 mol%
PCy3 and powdered K2CO3 in DMF. The C–X/C–H cross coup- deacylation was observed and the natural alkaloid, calothrixin
ling reaction proceeded as expected and 13 was isolated in B (2), was obtained in 85% yield.
90% yield after purification.18 CAN was found to be a very
After the successful completion of the calothrixin B (2) syn-
effective reagent for the oxidation of phenanthridine 13 to thesis via the iterative process, we focussed our attention
afford the corresponding quinone. However, during the oxi- towards the synthesis of 2 under double intramolecular C–X/
dative demethylation of 13, concomitant aromatization as well C–H cross coupling reaction conditions (Scheme 5). Although
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the use of the C–H activation methodology was initially
planned for the construction of the C7a–C7b bond, owing to
the high Pd(II) loading required for the reactions, an intra-
molecular multiple C–X/C–H cross coupling reaction was utilized
for the synthesis of 2, instead of the C–H activation
methodology.
The reductive amination of 4-((2-bromophenyl)amino)-2,5-
dimethoxybenzaldehyde (5b) with 2-iodoaniline (10) was then
carried out with sodium triacetoxyborohydride in the presence
of TFA in isopropyl acetate solvent and afforded 14 in 95%
yield. The intermediate 14 has all the structural requisites for
carrying out the multifold C–X/C–H cross coupling reaction to
construct the framework of the alkaloid 2. The acylation of 14
with acetyl chloride in the presence of triethylamine exclu-
sively afforded 4 and no trace of the diacetyl product was
observed in this reaction. The double intramolecular C–X/C–H
cross coupling reaction was then attempted on 4 under several
conditions and the best yield was obtained when the reaction
was carried out with 5 mol% of Pd(OAc)2 in the presence of
30 mol% of PCy3 and 10 mol% of JohnPhos. The reaction went
smoothly when performed with 4 equiv. of powdered K2CO3 in
DMF at 110 °C. The progress of the reaction was monitored by
LCMS, which clearly confirmed the early formation of the
C13a–C1a bond leading to the phenanthridine framework,
followed by C7a–C7b bond construction. This is probably due
to the lower activation energy required for the insertion of the
transition metal at the C13 position, because of the presence
of an adjacent N-acetyl group. The oxidative demethylation,
deacylation and further aromatization of 13 were carried out
with CAN in a single pot reaction and produced the natural
alkaloid 2 in good yield.
Scheme 7 Synthesis of murrayaquinone
A (3) via intramolecular
C–X/C–H cross coupling reaction. Reagents and conditions: (i) TMSCl,
TES, MeCN, r.t., 6 h, 80%; (ii) CAN, MeCN–water, r.t., 2 h, 88%; (iii)
Pd(OAc)2, K2CO3, 10 mol% JohnPhos, 20 mol% PCy3, MeCN, 110 °C, 9 h,
88%.
In an alternative attempt to synthesize murrayaquinone 3
(Scheme 7), 4-((2-bromophenyl)amino)-2,5-dimethoxybenz-
aldehyde (5b) was reduced with TES/TMSCl conditions to
afford 16.
CAN oxidation of 16 followed by intramolecular C–X/C–H
reaction using Pd(OAc)2, PCy3, JohnPhos and powdered K2CO3
afforded the natural alkaloid murrayaquinone A (3) in 88%
yield.
Conclusion
In conclusion, two efficient protocols for the synthesis of calo-
thrixin B (2) have been developed in overall excellent yields.
These syntheses were achieved through the development of
efficient mono and double C–X/C–H cross coupling reactions
through the exploration of various palladium catalysts and
ligands. Utilizing C–H activation as well as intramolecular
C–X/C–H reaction protocols, murrayaquinone A (3) has also
been synthesized. Studies are underway to expand the scope
of these methodologies for the synthesis of more complex
bisindole alkaloids.
As part of these studies, we also synthesized murrayaqui-
none
A (3) (Scheme 6). The carbazole-3-carbaldehyde 9
obtained by C–H activation of 5a was subjected to reduction
with TMSCl/TES to yield 3-methyl-9H-carbazole 15. Owing to
the decomposition of 15 under CAN oxidation conditions,19
the demethylative oxidation of 15 was attempted with boron
tribromide under aerial oxidation conditions as reported by
Moody et al.20 and the alkaloid 3 was isolated in 74% yield.
Experimental section
General
All reactions were carried out in oven dried glassware under an
atmosphere of N2, with magnetic stirring and the reactions
were monitored by TLC, using Merck aluminum-backed plates
pre-coated with silica (0.25 mm, 60, F254). The TLC plates
were visualized under UV light (254 nm) or developed using a
solution of KMnO4. Purifications were performed by column
chromatography (CC) with silica gel (60–120 mesh) purchased
from SRL and eluted with hexanes–EtOAc.
Mps were determined on an Electrothermal melting point
apparatus and are uncorrected. Infrared spectra were recorded
on a Perkin-Elmer 1650 Fourier Transform spectrometer. NMR
Scheme 6 Synthesis of murrayaquinone
Reagents and conditions: (i) Pd(OAc)2, AcOH, 130 °C, 6 h, 91%; (ii)
TMSCl, TES, MeCN, r.t., 4 h, 83%; (iii) BBr3, CH2Cl2, −78 °C, 22 h, 74%.
A (3) by C–H activation.
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spectra were measured in CDCl3, CD3OD or DMSO-D6 (all with 3H), 3.86 (s, 3H), 6.75 (s, 1H), 7.08 (td, J = 2.9, 5.4 Hz, 1H), 7.17
TMS as an internal standard) on Varian Gemini 400 MHz FT (s, 1H), 7.34–7.39 (m, 4H), 8.27 (s, 1H) and 10.09 (s, 1H). δC
magnetic resonance spectrometers. Chemical shifts are (DMSO-d6, 100 MHz) 55.8, 55.8, 94.8, 107.9, 114.3, 121.5 (2C),
reported in ppm, and coupling constants (J) are in Hz. The 123.1, 129.2 (2C), 140.2, 141.6, 141.8, 158.6 and 185.4. LRMS
following abbreviations were used to explain the multiplicities: (ESI): m/z = 258 (M + H)+. HRMS (ESI) calcd for C15H16NO3
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. (M + H)+: 258.1130, found: 258.1139.
Mass spectra were recorded on an HP-5989A quadrupole mass
spectrometer.
Procedure for the preparation of 1,4-dimethoxy-9H-carbazole-
3-carbaldehyde (9)
Procedure for 4-iodo-2,5-dimethoxybenzaldehyde (6)
From 2,5-dimethoxy-4-(phenylamino)benzaldehyde (5a). A
A
mixture of 2,5-dimethoxybenzaldehyde
7
(10.2 g, mixture of 2,5-dimethoxy-4-(phenylamino)benzaldehyde (5a)
61.4 mmol), silver nitrate (10.4 g, 61.4 mmol), and iodine (0.5 g, 1.9 mmol) and palladium(II) acetate (0.873 g, 3.9 mmol)
(16.2 g, 64 mmol) in 250 mL of methanol was stirred under in glacial acetic acid (10 mL) was heated to 130 °C for 6 hours
nitrogen overnight. The yellow precipitate was filtered and with gentle stirring under argon atmosphere. After the com-
washed with methanol. The remaining iodine was reduced pletion of the reaction, the mixture was cooled to room temp-
with saturated sodium bisulfite solution and the solvent was erature and poured into aqueous sodium hydrogen carbonate
removed on a rotary evaporator and the residue recrystallized solution (25 mL). Solid sodium hydrogen carbonate was added
from 95% ethanol to yield the off-white title compound 6 to the reaction mixture till it was neutral. The reaction mixture
(17.08 g, 95%).
was extracted with EtOAc (3 × 30 mL) and the layers were separ-
Mp: 139–141 °C.15 IR (νmax/cm−1) 3410, 2942, 1676, 1595, ated. The organic layer was concentrated under reduced
1386, 1216, 1035 and 770. δH (CDCl3, 400 MHz) 3.87 (s, 3H), pressure and the crude product was purified by flash chrom-
3.89 (s, 3H), 7.22 (s, 1H), 7.47 (s, 1H) and 10.40 (s, 1H). δC atography on silica gel (EtOAc–petroleum ether = 1 : 5) which
(CDCl3, 100 MHz) 56.6, 56.7, 97.0, 107.5, 124.0, 124.3, 152.2, gave the title compound 9 as a pale yellow solid (0.449 g,
155.7 and 188.4. LRMS (ESI) m/z = 293 (M + H)+. HRMS (ESI) 91%).
calcd for C9H10IO3 (M + H)+: 292.9675, found: 292.9674.
From 4-((2-bromophenyl)amino)-2,5-dimethoxybenzaldehyde
(5b). A mixture of 4-((2-bromophenyl)amino)-2,5-dimethoxy-
benzaldehyde (5b) (1 g, 2.9 mmol), powdered K2CO3 (0.823 g,
5.9 mmol), palladium(II) acetate (0.033 g, 0.1 mmol), tricyclo-
Procedure for the preparation of 4-((2-bromophenyl)amino)-
2,5-dimethoxybenzaldehyde (5b)
A mixture of 4-iodo-2,5-dimethoxybenzaldehyde (6) (10 g, hexylphosphine (0.167 g, 0.6 mmol) and 10 mol% of (2-biphe-
34 mmol), 2-bromoaniline 8b (5.9 g, 34 mmol), Pd(dppf)- nyl)di-tert-butylphosphine (JohnPhos) (0.089 g, 0.3 mmol) in
Cl2·CH2Cl2 (1.40 g, 1.7 mmol), ( )-2,2-bis(diphenylphosphino)- acetonitrile (20 mL) was heated 100 °C for 12 hours with
1,1′-binaphthyl [( )-BINAP] (1.06 g, 1.7 mmol) and cesium car- gentle stirring under argon atmosphere. After completion of
bonate (22 g, 68 mmol) in acetonitrile (150 mL) was stirred at the reaction, the mixture was filtered over a celite bed and
60–70 °C under N2 for 12 hours (the reaction was monitored washed with EtOAc. The organic layer was concentrated under
by TLC). The reaction mixture was filtered over a celite bed and reduced pressure and the crude product was purified by flash
washed with EtOAc. The organic layer was concentrated under chromatography on silica gel (EtOAc–petroleum ether = 1 : 5)
reduced pressure and the crude product was purified by flash which gave the title compound 9 as a pale yellow solid
chromatography on silica gel (EtOAc–petroleum ether
1 : 10) which gave the title compound 5b as a pale yellow solid
(9.8 g, 85%).
=
(0.679 g, 90%).
Mp: 173–175 °C. IR (νmax/cm−1) 3349, 2851, 1657, 1622,
1586, 1340. δH (DMSO-d6, 400 MHz) 4.02 (s, 3H), 4.09 (s, 3H),
Mp: 124–126 °C. IR (νmax/cm−1) 3398, 3019, 2400, 1657, 7.24 (s, 1H), 7.31 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 7.3 Hz, 1H),
1584, 1525, 1215. δH (CDCl3, 400 MHz) 3.79 (s, 3H), 3.95 (s, 7.57 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 10.36 (s, 1H)
3H), 6.72 (s, 1H), 6.93–7.01 (m, 2H), 7.26–7.35 (m, 2H), 7.53 (d, and 12.09 (s, 1H). δC (DMSO-d6, 100 MHz) 55.8, 63.7, 102.4,
J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H) and 10.26 (s, 1H). δC 112.1, 115.8, 119.8, 120.5, 120.9, 122.1, 126.0, 135.8, 139.7,
(CDCl3, 100 MHz) 56.1, 56.2, 95.6, 108.2, 116.3, 116.8, 121.2, 142.7, 155.4 and 187.8. LRMS (ESI): m/z = 256 (M + H)+. HRMS
124.6, 128.2, 133.6, 138.2, 140.3, 141.9, 158.9 and 187.4. LRMS (ESI) calcd for C15H14NO3 (M + H)+: 256.0974, found: 256.0973.
(ESI): m/z = 336, 338 (M + H)+. HRMS (ESI) calcd for
Procedure for N-((1,4-dimethoxy-9H-carbazol-3-yl)methyl)-
2-iodoaniline (11)
C15H15BrNO3 (M + H)+: 336.0235, found: 336.0231.
Procedure for the preparation of 2,5-dimethoxy-4-
(phenylamino)benzaldehyde (5a)
A round bottomed flask was charged with 2-iodoaniline (10)
(0.24 g, 1.1 mmol) and 1,4-dimethoxy-9H-carbazole-3-carbalde-
The compound 5a was prepared as shown in the general hyde (9) (0.28 g, 1.1 mmol) followed by i-PrOAc (6 mL) and
experimental procedure for 5b and isolated as an off-white trifluoroacetic acid (0.250 g, 2.2 mmol). Sodium triacetoxyboro-
solid (7.9 g, 90%).
hydride (0.465 g, 2.2 mmol) was added as a solid over 2 min
Mp: 122–124 °C. IR (νmax/cm−1) 3778, 3411, 3019, 2905, (an exothermicity was observed up to ∼40 °C). After 10 min
2834, 1656, 1497, 1275, 1216. δH (DMSO-d6, 400 MHz) 3.74 (s, agitation, TLC showed the completion of the reaction. The
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reaction mixture was diluted with EtOAc (20 mL). A solution of After 10 min agitation TLC showed the completion of the reac-
2 wt% of aqueous NaOH was added into the reaction mixture tion. The reaction mixture was diluted with ethyl acetate
until pH 8–9. The layers were separated and the organic layer (30 mL). A solution of 2 wt% of aqueous NaOH was added into
was washed with brine and dried over Na2SO4. The organic the reaction mixture until pH 8–9. The layers were separated
layer was concentrated under reduced pressure to afford the and the organic layer was washed with brine, dried over
crude product which was purified by flash chromatography on Na2SO4 and concentrated under reduced pressure to afford the
silica gel (EtOAc–petroleum ether = 2 : 5), which gave the title crude product. The crude product was purified by flash chrom-
compound 11 as a pale brown gummy liquid (0.477 g, 95%).
atography on silica gel (EtOAc–petroleum ether = 2 : 5) to give
IR (νmax/cm−1) 3584, 3392, 2921, 1589, 1449, 1219. δH the title compound 14 as a dark brown gummy liquid (0.764 g,
(DMSO-d6, 400 MHz) 3.90 (s, 3H), 3.95 (s, 3H), 4.52 (d, J = 5.4 95%).
Hz, 2H), 5.23 (t, J = 5.9 Hz, 1H), 6.38 (t, J = 6.4 Hz, 1H), 6.74 (d,
IR (νmax/cm−1) 3584, 3393, 3019, 2918, 1588, 1456, 1217.
J = 8.4 Hz, 1H), 6.99 (s, 1H), 7.12–7.21 (m, 2H), 7.37 (t, J = δH (DMSO-d6, 400 MHz) 3.69 (s, 3H), 3.77 (s, 3H), 4.31 (d, J =
7.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 5.9 Hz, 2H), 5.20 (t, J = 5.9 Hz, 1H), 6.39 (t, J = 7.8 Hz, 1H), 6.63
8.09 (d, J = 7.4 Hz, 1H) and 11.41 (s, 1H). δC (DMSO-d6, (t, J = 7.8 Hz, 1H), 6.69 (s, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.86 (s,
100 MHz) 55.7, 59.7, 61.0, 85.1, 106.9, 111.1, 111.3, 116.1, 1H), 7.02 (s, 1H), 7.10–7.17 (m, 2H), 7.24 (t, J = 7.8 Hz, 1H),
118.3, 119.0, 120.5, 120.7, 121.9, 125.2, 129.7, 130.2, 138.6, 7.57 (d, J = 7.9 Hz, 1H) and 7.63 (d, J = 7.9 Hz, 1H). δC (DMSO-
139.6, 142.1, 146.8 and 147.4. LRMS (ESI): m/z = 457 (M − H)+. d6, 100 MHz) 42.3, 55.9, 56.2, 85.2, 103.3, 111.2, 112.3, 112.9,
240 (M − iodoaniline). HRMS (ESI) calcd for C21H18IN2O2 116.9, 118.3, 120.1, 121.3, 128.5, 129.3, 130.0, 132.7, 138.7,
(M − H)+: 457.0413, found: 457.0417.
140.9, 143.8, 147.3 and 151.1. LRMS (ESI): m/z = 537, 538, 539,
540, 541 (M + H)+. HRMS (ESI) calcd for C21H21BrIN2O2
(M + H)+: 538.9831, found: 538.9850.
Procedure for N-((1,4-dimethoxy-9H-carbazol-3-yl)methyl)-
N-(2-iodophenyl)acetamide (12)
Preparation of N-(4-((2-bromophenyl)amino)-2,5-
dimethoxybenzyl)-N-(2-iodophenyl)acetamide (4)
A round bottomed flask was charged with N-((1,4-dimethoxy-
9H-carbazol-3-yl)methyl)-2-iodoaniline (11) (0.41 g, 0.89 mmol)
and triethylamine (0.135 g, 1.33 mmol) in dichloromethane A round bottomed flask was charged with N-(2-bromophenyl)-
(5 mL) and cooled to below 5 °C. Freshly distilled acetyl chlor- 4-(((2-iodophenyl)amino)methyl)-2,5-dimethoxyaniline (14)
ide was slowly added (0.084 g, 1.07 mmol). The reaction was (0.5 g, 0.92 mmol) and triethylamine (0.141 g, 0.14 mmol) in
stirred at room temperature for 2 hours. After completion dichloromethane (20 mL) and cooled to below 5 °C. Freshly
of the reaction, ice cold water was added into the reaction distilled acetyl chloride was slowly added (0.088 g, 1.1 mmol).
mixture and extracted with 3 × 20 mL of dichloromethane. The The reaction was stirred at room temperature for 2 hours. After
organic layer was washed with brine, and dried over Na2SO4. the completion of the reaction, ice cold water was added into
The organic layer was concentrated under reduced pressure to the reaction mixture and extracted with 3 × 30 mL of dichloro-
afford the crude product which was purified by flash chrom- methane and the organic layer was washed with brine and
atography on silica gel (EtOAc–petroleum ether = 0.5 : 10) to dried over Na2SO4. The organic layer was concentrated under
give the title compound 12 as a pale yellow gummy liquid reduced pressure to afford the crude product which was puri-
(0.423 g, 94%).
fied by flash chromatography on silica gel (EtOAc–petroleum
IR (νmax/cm−1) 3778, 3584, 3469, 2401, 1648, 1470, 1305, ether = 0.5 : 10) to give the title compound 4 as a brown
1215. δH (CDCl3, 400 MHz) 1.87 (s, 3H), 3.54 (s, 3H), 3.94 (s, gummy liquid (0.505 g, 94%).
3H), 4.52 (d, J = 14.2 Hz, 1H), 5.71 (d, J = 14.2 Hz, 1H), 6.69
IR (νmax/cm−1) 3778, 3399, 3019, 2400, 1648, 1524, 1215. δH
(dd, J = 7.8 Hz, 1H), 6.92 (s, 1H), 6.95 (t, J = 7.8 Hz, 1H), 7.06 (t, (DMSO-d6, 400 MHz) 1.71 (s, 3H), 3.40 (s, 3H), 3.71 (s, 3H),
J = 7.8 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.37–7.45 (m, 2H), 7.91 4.29 (d, J = 14.2 Hz, 1H), 5.13 (d, J = 14.2 Hz, 1H), 6.54 (s, 1H),
(dd, J = 7.8 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H) and 8.32 (s, 1H). δC 6.68 (s, 1H), 6.73–6.79 (m, 1H), 6.81 (s, 1H), 7.02 (d, J = 6.4 Hz,
(CDCl3 100 MHz) 23.0, 44.7, 54.9, 56.0, 100.4, 108.3, 110.8, 1H), 7.05–7.11 (m, 2H), 7.23 (t, J = 8.3 Hz, 1H), 7.34 (t, J = 7.4
119.5, 119.8, 121.9, 122.6 (2C), 125.4 (2C), 129.2, 130.7 (2C), Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H) and 7.96 (d, J = 7.8 Hz, 1H). δC
138.9, 140.0, 144.4, 147.1, 154.3 and 170.4. LRMS (ESI): m/z = (DMSO-d6, 100 MHz) 22.7, 44.8, 55.7, 56.2, 101.2, 102.9, 112.6,
501 (M + H)+. HRMS (ESI) calcd for C23H22IN2O3 (M + H)+: 114.3, 117.2, 117.5, 121.5, 128.4, 129.2, 129.8, 130.6, 130.7,
501.0675, found: 501.0696.
132.8, 139.4, 140.8, 143.5, 144.2, 151.5 and 168.8. LRMS (ESI):
m/z = 579.9, 580.9, 582.99, 583.99 (M + H)+. HRMS (ESI) calcd
for C23H23N2O3BrI (M + H)+: 580.9937, Found: 580.9914
Preparation of N-(2-bromophenyl)-4-(((2-iodophenyl)amino)-
methyl)-2,5-dimethoxyaniline (14)
Preparation of 1-(7,13-dimethoxy-6,12-dihydro-5H-indolo-
[3,2-j]phenanthridin-5-yl)ethanone (13)
A round bottomed flask was charged with 2-iodoaniline (10)
(0.358 g, 1.5 mmol) and 4-((2-bromophenyl)amino)-2,5-
dimethoxybenzaldehyde (5b) (0.5 g, 1.5 mmol) followed by
From N-((1,4-dimethoxy-9H-carbazol-3-yl)methyl)-N-(2-iodo-
i-PrOAc (10 mL) and trifluoroacetic acid (0.339 g, 3 mmol). phenyl)acetamide (12). To a solution of N-((1,4-dimethoxy-9H-
Sodium triacetoxyborohydride (0.630 g, 3 mmol) was added as carbazol-3-yl)methyl)-N-(2-iodophenyl)acetamide (12) (0.2 g,
a solid over 2 min (exothermicity was observed up to ∼40 °C). 0.4 mmol) in degassed dry DMF (6 mL), PCy3 (0.025 g,
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0.08 mmol), anhydrous powdered K2CO3 (0.110 g, 0.8 mol) (M + H)+. HRMS (ESI) calcd for C19H11N2O2 (M + H)+:
and Pd(OAc)2 (0.005 g, 0.02 mmol) were added. The reaction 299.0821, found: 299.0811.
mixture was stirred at 110 °C under argon atmosphere for
10 hours (the reaction was monitored by TLC). The reaction
mixture was cooled to room temperature and filtered over a
celite bed and washed with EtOAc (10 mL). The combined
organic layer was concentrated under reduced pressure to yield
the crude product. The crude product was purified by flash
chromatography on silica gel (EtOAc–petroleum ether = 2.5 : 5)
which gave the desired compound as a brown solid 13
(1.034 g, 90%).
From N-(4-((2-bromophenyl)amino)-2,5-dimethoxybenzyl)-N-
(2-iodophenyl)acetamide (4). To a solution of N-(4-((2-bromo-
phenyl)amino)-2,5-dimethoxybenzyl)-N-(2-iodophenyl)acetamide
(4) (0.5 g, 0.86 mmol) in degassed dry DMF (6 mL), PCy3
(0.072 g, 0.25), JohnPhos (0.025 g, 0.08 mmol), anhydrous
powdered K2CO3 (0.475 g, 3.5 mmol) and Pd(OAc)2 (0.010 g,
0.04 mmol) were added. The reaction mixture was stirred at
110 °C under argon atmosphere for 10 hours (the reaction was
monitored by TLC). The reaction mixture was cooled to room
temperature and filtered over a celite bed and washed with
EtOAc (10 mL). The combined organic layer was concentrated
under reduced pressure to yield the crude product. The crude
product was purified by flash chromatography on silica gel
(EtOAc–petroleum ether = 2.5 : 5) which gave the desired com-
pound as a brown solid 13 (0.280 g, 88%).
Preparation of 1,4-dimethoxy-3-methyl-9H-carbazole (15)
A round bottomed flask was charged with triethylsilane
(0.683 g, 5.8 mmol) and trimethylsilyl chloride (0.532 g,
4.9 mmol) under a nitrogen atmosphere. Then a solution of
1,4-dimethoxy-9H-carbazole-3-carbaldehyde
(9)
(0.5
g,
1.9 mmol) in acetonitrile (5 mL) was added slowly at room
temperature and stirred for 4 hours. After completion of the
reaction, water (10 mL) was added and the volatiles were
removed under vacuum. The reaction mixture was extracted
with 3 × 20 mL of EtOAc and the combined organic layer was
washed with brine, dried over Na2SO4 and concentrated under
reduced pressure to afford the crude product. The crude
product was purified by flash chromatography on silica gel
(EtOAc–petroleum ether = 0.5 : 5) which gave the title com-
pound 15 as an orange solid (0.393 g, 83%).
Mp: 99–101 °C 19 (reported 98–100 °C). IR (νmax/cm−1) 3863,
3404, 3019, 2905, 2834, 1720, 1602, 1426, 1215. δH (CDCl3,
400 MHz) 2.37 (s, 3H), 3.88 (s, 6H), 6.61 (s, 1H), 7.15 (ddd, J =
6.9 and 2.0 Hz, 1H), 7.31 (m, 2H) and 8.14 (d, J = 7.8 Hz, 2H).
δC (CDCl3, 100 MHz) 15.4, 55.8, 60.2, 108.8, 110.6, 117.3,
119.5, 120.1, 122.0, 122.6, 125.3, 129.3, 139.1, 141.7 and 147.1.
LRMS (ESI): m/z = 242 (M + H)+. HRMS (ESI) calcd for
C15H16NO2 (M + H)+: 242.1181, found: 242.1175.
Mp: 239–241 °C. IR (νmax/cm−1) 3231, 2837, 1734, 1638,
1624, 1396. δH (DMSO-d6, 400 MHz) 2.11 (s, 3H), 3.82 (s, 3H),
3.98 (s, 3H), 4.5–5.2 (b, 2H), 7.23 (t, J = 7.7 Hz, 1H), 7.41–7.46
(m, 3H), 7.55 (d, J = 8.0 Hz, 2H), 8.11 (d, J = 7.7 Hz, 1H), 8.46
(m, 1H) and 11.59 (s, 1H). δC (DMSO-d6, 100 MHz) 22.0, 60.3,
61.0, 111.3 (2C), 116.3, 119.4 (2C), 120.7 (2C), 122.0 (2C), 125.0
Preparation of N-(2-bromophenyl)-2,5-dimethoxy-4-
methylaniline (16)
(2C), 125.9, 127.7, 134.0, 138.5, 139.4, 140.2, 146.4 and 168.2. A round bottomed flask was charged with triethylsilane
LRMS (ESI): m/z = 373 (M + H)+. HRMS (ESI) calcd for (1.01 g, 8.7 mmol) and trimethylsilyl chloride (0.793 g,
C23H21N2O3 (M + H)+: 373.1552, found: 373.1548
7.3 mmol) under a nitrogen atmosphere. Then a solution of
4-((2-bromophenyl)amino)-2,5-dimethoxybenzaldehyde (5b)
(1 g, 2.9 mmol) in acetonitrile (10 mL) was added slowly at
room temperature and stirred for 6 hours. After completion of
Preparation of calothrixin B (2)
To a stirred solution of compound 13 (0.2 g, 0.54 mmol) in the reaction, water (10 mL) was added and the volatiles
acetonitrile (5 mL) and water (5 mL), ceric ammonium nitrate were removed under vacuum. The mixture was extracted with
(CAN) (0.740 g, 1.35 mmol) was added. The reaction mixture 3 × 20 mL of EtOAc and the combined organic layer was
was stirred at room temperature for 2 hours. After completion washed with brine, dried over Na2SO4 and concentrated
of the reaction, water (20 mL) was added into the reaction under reduced pressure to afford the crude product. The
mixture and extracted with EtOAc (3 × 20 mL). The organic crude product was purified by flash chromatography on
layer was concentrated under reduced pressure to afford the silica gel (EtOAc–petroleum ether = 1 : 10) which gave the
crude product. The crude product was purified by flash chrom- title compound 16 as a light brown gummy liquid (0.770 g,
atography on silica gel (EtOAc–petroleum ether = 0.4 : 10) 80%).
which afforded red calothrixin B (2) (0.137 g, 85%).
IR (νmax/cm−1) 3863, 3404, 3019, 2905, 2834, 1720, 1602,
Mp: >300 °C.4 IR (νmax/cm−1) 3863, 3404, 3019, 2905, 2834, 1426, 1215. δH (DMSO-d6, 400 MHz) 2.09 (s, 3H), 3.69 (s, 3H),
1720, 1602, 1426, 1215. δH (DMSO-d6, 400 MHz) 7.40 (t, J = 3.74 (s, 3H), 6.59 (s, 1H), 6.74 (t, J = 7.8 Hz, 1H), 6.81 (s, 1H),
7.8 Hz, 1H), 7.48 (t, J = 8.3 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 6.91 (s, 1H), 6.99 (d, J = 8.3 Hz, 1H), 7.20 (t, J = 8.3 Hz, 1H) and
7.89 (t, J = 8.3 Hz, 1H), 7.95 (t, J = 8.3 Hz, 1H), 8.16–8.19 (m, 7.54 (d, J = 7.8 Hz, 1H). δC (CDCl3, 100 MHz) 15.9, 56.2, 56.5,
2H), 9.58 (d, J = 8.3 Hz, 1H), 9.63 (s, 1H) and 13.17 (s, 1H). 103.3, 112.6 and 114.5, 115.5, 120.1, 120.6, 128.0, 128.9, 133.0,
δC (DMSO-d6, 100 MHz) 113.9, 115.5, 122.3, 122.6, 123.3, 141.6, 144.1, 151.5. LRMS (ESI): m/z = 322, 324 (M + H)+.
124.4, 124.9, 127.2 (2C), 129.8, 130.3, 131.6, 132.7, 138.0, HRMS (ESI) calcd for C15H17BrNO2 (M + H)+: 322.0443, found:
138.4, 147.5, 151.2, 180.4 and 180.9. LRMS (ESI): m/z = 299 322.0435.
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Organic & Biomolecular Chemistry
Preparation of 2-((2-bromophenyl)amino)-5-methylcyclohexa-
2,5-diene-1,4-dione (17)
Acknowledgements
The authors would like to thank Dr Vilas H. Dahanukar for his
constant encouragement and support. We also thank the
analytical department of Dr Reddy’s Laboratories, for provid-
ing analytical support.
To a stirred solution of N-(2-bromophenyl)-2,5-dimethoxy-4-
methylaniline (16) (0.7 g, 2.2 mol) in acetonitrile (15 mL) and
water (15 mL), CAN (3 g, 5.4 mol) was added. The reaction
mixture was stirred at room temperature for 2 hours. After
completion of the reaction, water (40 mL) was added into the
reaction mixture and extracted with EtOAc (3 × 30 mL). The
organic layer was concentrated under reduced pressure to Notes and references
give the crude product. The crude product was purified
1 R. W. Rickards, J. M. Rothschild, A. C. Willis, N. M. de
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by flash chromatography on silica gel (EtOAc–petroleum
ether = 0.2 : 10) which afforded the red title compound
(0.559 g, 88%).
Mp 231–233 °C. IR (νmax/cm−1) 3434, 3306, 2954, 2919,
2346, 1735, 1670, 1530, 1223. δH (DMSO-d6, 400 MHz) 1.97 (s,
3H), 5.24 (s, 1H), 6.72 (s, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.41 (d,
J = 8.0 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H)
and 8.71 (s, 1H). δC (DMSO-d6, 100 MHz) 16.3, 101.8, 117.4,
122.7, 126.2, 128.3, 129.5, 133.5, 135.8, 142.3, 149.3, 183.3 and
186.8. LRMS (ESI): m/z = 291.9, 293.9 (M + H)+. HRMS (ESI)
calcd for C13H11BrNO2 (M + H)+: 291.9973, found: 291.9968.
6 (a) P. H. Bernardo and C. L. L. Chai, J. Org. Chem., 2003,
68, 8906; (b) N. Ramkumar and R. Nagarajan, J. Org. Chem.,
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Preparation of murrayaquinone A (3)
From 1,4-dimethoxy-3-methyl-9H-carbazole (15). A solution
of 1,4-dimethoxy-3-methyl-9H-carbazole (15) (0.3 g, 1.2 mmol)
in dichloromethane (5 mL) was cooled to −78 °C. Boron tribro-
mide in dichloromethane (1 M; 2.5 mL, 2.4 mmol) was added
at −78 °C and the mixture was stirred for 22 hours at room
temperature under air. The reaction mixture was then poured
into ice–water (10 mL) and the product was extracted into
EtOAc (3 × 20 mL). The organic layer was separated, dried over
Na2SO4 and concentrated under reduced pressure to afford
the crude product. The crude product was purified by flash 10 M.-L. Bennasar, T. Roca and F. Ferrando, Org. Lett., 2006, 8,
chromatography on silica gel (EtOAc–petroleum ether = 1 : 5)
which afforded the red title compound (0.194 g, 74%).
561–564.
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Tetrahedron, 2007, 63, 10963; (b) A. Yamabuki, H. Fujinawa,
T. Choshi, S. Tohyama, K. Matsumoto, K. Ohnuma,
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5859; (c) J. Sperry, C. S. P. McErlean, A. M. Z. Slawin and
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From 2-((2-bromophenyl)amino)-5-methylcyclohexa-2,5-
diene-1,4-dione (17). A mixture of 2-((2-bromophenyl) amino)-
5-methylcyclohexa-2,5-diene-1,4-dione (17) (0.1 g, 0.34 mmol),
anhydrous powdered K2CO3 (0.094 g, 0.68 mmol), palladium(II)
acetate (0.038 g, 0.02 mmol), tricyclohexylphosphine (0.019 g,
0.07 mmol) and 10 mol% of JohnPhos (0.010 g, 0.03 mol) in 12 T. S. Wu, T. Ohta and H. Furukawa, Heterocycles, 1983, 20,
acetonitrile (5 mL) was heated to 110 °C under argon atmos- 1267.
phere for 9 hours. The reaction mixture was filtered over a 13 (a) L. F. Tietze and A. Dufrt, Pure Appl. Chem., 2010, 82,
celite bed and washed with EtOAc. The combined organic layer
was concentrated under reduced pressure and the crude
product was purified by flash chromatography on silica gel
(EtOAc–petroleum ether = 1 : 5) which gave the red title
compound 3 (0.064 g, 88% yield).
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)
3863, 3404, 3019, 2905, 2834, 1720, 1602, 1426, 1215. 15 B. A. Hathaway, B. E. Taylor and J. S. Wittenbom, Synth.
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1H) and 9.18 (br s, 1H). δC (CDCl3 + DMSO-d6 100 MHz) 20.9,
118.8, 120.7, 126.7, 128.6, 128.8, 131.0, 136.6, 141.0, 142.7,
153.0, 185.1 and 188.1. LRMS (ESI): m/z = 212 (M + H)+.
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This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6105–6113 | 6113