Total synthesis of calothrixin A and B via C-H activation

Article abstract of DOI:10.1021/jo302821v

Bioactive indolo[3,2-j]phenanthridine alkaloids Calothrixin A and B have been synthesized by exploiting Pd-catalyzed cross-coupling reaction via C-H activation as a key step starting from 4-methoxycarbazole.

Full text of DOI:10.1021/jo302821v

Note
pubs.acs.org/joc
Total Synthesis of Calothrixin A and B via C−H Activation
Nagarajan Ramkumar and Rajagopal Nagarajan*
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
S
* Supporting Information
ABSTRACT: Bioactive indolo[3,2-j]phenanthridine alkaloids
Calothrixin A and B have been synthesized by exploiting Pd-
catalyzed cross-coupling reaction via C−H activation as a key
step starting from 4-methoxycarbazole.
he novel indolo[3,2-j]phenanthridine alkaloids, Calothrix-
in A (1) and B (2) (Figure 1) were originally isolated
Scheme 1. Retrosynthetic Analysis to Calothrixin B (2)
T
Figure 1. Calothrixin A (1) and B (2).
from Calothrix cyanobacteria and extensively studied by
Rickards’s group in 1999.1 These unique pentacyclic alkaloids
show potent antimalarial activity, inhibition of RNA polymer-
ase, as well as DNA topoisomerase I poisoning activity and
antiproliferative properties against human HeLa cancer cells.2
Owing to their novel structural scaffolds and potential
biological activities, calothrixins are remarkable synthetic targets
for total synthesis.4 In 2000, the first total synthesis of
calothrixins was reported by Kelly,3 employing ortho-lithiation
strategies, and several synthetic methods4 have been reported
later including two biosynthetic routes.5 In this context, we
outlined a route to the synthesis of 1 and 2, in which the
quinoline ring would be constructed from an appropriately
substituted carbazole in the last synthetic steps by Pd-catalyzed
intramolecular cross-coupling reaction via C−H activation. In
this manner, a C−C bond is formed by activating the C2
position of the carbazole skeleton (C13a−C13bbond formed) to
make the indolo[3,2-j]phenanthridine core system, which could
be considered as a prominent step (scheme 1).
The retrosynthetic analysis of 2 shown in Scheme 1. We
envisaged that amides 6 (C6−C5, bond a) and 16 (C6a−C6,
bond b) could be synthesized from 4-methoxycarbazole 3 in
two different methods. By Pd-catalyzed reaction 7, 8, and 16
were converted into indolophenanthridinones 9, 13, and 17
through intramolecular C−H/C-I and C−H/C-H (C13a-C13b
,
bond c) cross coupling via C−H activation. Subsequently,
compounds 9, 13, and 17 would be easily transformed into
calothrixin B 2 through phenols 11 and 15.
Our investigation began with the synthesis of precursors 7
and 8, a model precursor bearing the required benzene moiety
connected to the third position of carbazole as functionalized
amide group. This compound was easily accessible from 3 as
depicted in Scheme 2. Vilsmeier−Haack formylation of 3 with
NMF/POCl3 in 1,2-dichlorobenzene at 70 °C for 3 h yielded
only 3-formylated product 4. Oxidation of 4 with 30% H2O2,
NaClO2, and KH2PO4 in THF/H2O (2:1) readily gave 4-
methoxycarbazole-3-carboxylic acid 5. Acid 5 was transformed
into amide 6 upon treatment with SOCl2 in dry CHCl3 at reflux
condition, followed by the addition of 2 equiv of K2CO3, 2-
iodoaniline in dry THF. Amide 6 was subsequently converted
into bis-N-protected compound 7 and amide N-protected
Transition-metal-catalyzed cross-coupling reactions6 are the
powerful tools for C−C bond formation in organic synthesis for
building molecular architectures and abound in the spectacular
synthesis of various naturally occurring alkaloids.7 Among
alkaloid total syntheses, methods utilizing Pd-catalyzed cross-
coupling reactions offer fascinate routes,8 and the combination
of palladium with other metals such as Cu and Ag proved to be
an alternative strategy to facilitate C−H activation of
substrates.9
Received: December 30, 2012
Published: February 20, 2013
© 2013 American Chemical Society
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Note
a
With pentacycle 9 in hand, the subsequent conversion into
12 was achieved in a three-step sequence (Scheme 4).
Reduction of indolo[3,2-j]phenanthridinone 9 with excess of
LiAlH4 in dry Et2O readily gave 10. Demethylation of 10 with
iodotrimethylsilane10 and catalytic amount of pyridine in
sulfolane at 70 °C for 20 h provided indolo[3,2-j]-
phenanthridinol 11. N-MOM calothrixin 12, a known
intermediate precursor of calothrixin B was prepared by
oxidation with molecular oxygen under basic condition.11
Removal of MOM group in the next step afforded 2 with
almost quantitative yield. Thus, we completed the synthesis of
calothrixin B with good overall yield of 30% over 10 steps.
To our knowledge, methods previously reported for the
synthesis of calothrixin B have shown that the indole nitrogen
atom was always initially protected and cleaved in the final step.
So we attempted a route to avoid the protection of the free
indole nitrogen of calothrixin B, which was attained from the
precursor 8 (scheme 5). The precursor 8 was subjected to our
Pd-catalyzed cross-coupling condition gave 13, which was then
treated with LAH followed by cleavage of methyl group with
TMSI to provide 15. Phenol 15, another known intermediate
precursor of calothrixin B, was converted into 2 by oxidation
with FeCl3.12 Finally, we achieved the synthesis of calothrixin B
without any substitution at indole nitrogen in a total of 9 steps,
in 27% overall yield from 4-methoxycarbazole. In addition,
selective oxidation of the pyridine nitrogen13 of the synthetic 2
with PhCN and TBHP/NaOH in acetone afforded calothrixin
A 1.
Scheme 2. Synthesis of Precursors 7 and 8
a
Reagents and conditions: (i) N-methylformanilide, POCl3, o-DCB,
70 °C, 3 h, 82%; (ii) 30% H2O2, NaClO2, KH2PO4, THF/H2O (2:1),
rt, 8 h, 97%; (iii) (a) SOCl2, CHCl3, reflux, 6 h, 95%; (b) 2-
iodoaniline, 2 equiv K2CO3, dry THF, rt, overnight, 96%; (iv) NaH,
MOMCl, dry THF, N2, 50 °C, 20 h, 92%. (v) P2O5, dimethoxy-
methane, dry CHCl3, rt, 8 h, 89%.
compound 8 by treatment with NaH, MOMCl in dry THF at
50 °C for 20 h and P2O5, dimethoxymethane in dry CHCl3 at
room temperature for 8 h, respectively.
Our ultimate goal is to carry out Pd-catalyzed cross-coupling
of bis-N-protected compound 7 to construct the indolo[3,2-
j]pheanthridine skeleton (Scheme 3) and subsequent con-
Though we have synthesized calothrixins by utilizing simple
methods with good yields, the methods comprise a greater
number of steps. Next, we attempted to reduce the number of
steps so that the overall yield will increase considerably and
become more concise. A short synthetic route to calothrixins is
outlined in Scheme 6. The precursor 16 was synthesized in one
pot by Friedel−Crafts acylation of 3 with oxalyl chloride in the
presence of AlCl3 in dry DCM followed by amidation with
aniline. Then we conducted the Pd-catalyzed intramolecular
oxidative coupling of 16. When amide 16 was heated at 120 °C
for 24 h in the presence of 5 mol % Pd(TFA)2 under an oxygen
atmosphere in melted benzoic acid, indolophenanthridinone 17
was obtained in 83%. After that 17 was subjected to
chemoselective reduction14 with Tf2O/Et3SiH to provide 14.
Indolophenanthridine 14 was then easily transformed into 2 in
a couple of steps that were shown in Scheme 5. Finally, we
accomplished the synthesis of 2 in a total of 5 steps over 35%
overall yield.
Scheme 3. Key Pd-Catalyzed Cross-Coupling Reaction
version to calothrixin B 2. This was achieved, when the reaction
of 7 in conjunction with 2 equiv of KOAc, 5 mol % Pd(OAc)2,
10 mol % Ag2O in DMF at 110 °C for 6 h afforded 9 with good
yield of 81%. Catalyst evaluation revealed that the presence of
Ag2O was important and proved to be a good promoter of
cross-coupling reaction between aryl iodide and sp2-carbon (2-
position) of the carbazole skeleton.
a
Scheme 4. Preparation of N-MOM Calothrixin B 12
a
Reagents and conditions: (i) LiAlH4, dry Et2O, rt, 3 h then 6 N HCl, 87%; (ii) TMSI, pyridine, sulfolane, 70 °C, 20 h then dry MeOH, 76%; (iii)
NaOH, O2, acetone, rt, 20 h, 88%; (iv) conc HCl, THF, 60 °C, 20 h, 98%.
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a
Scheme 5. Synthesis of Calothrixin B (2) and A (1)
a
Reagents and conditions: (i) 3 equiv KOAc, 5 mol % Pd(OAc)2, 10 mol % Ag2O, DMF, 110 °C, 8 h, 74%; (ii) LiAlH4, dry Et2O, rt, 3 h then 6 N
HCl, 92−96%; (iii) TMSI, pyridine, sulfolane, 70 °C, 20 h then dry MeOH, 81−86%; (iv) FeCl3, cat. 2,6-dicarboxypyridine 1-oxide, 70% aq TBHP,
tert-amyl alcohol, rt, 8 h, 71%; (v) PhCN, TBHP/NaOH, acetone, rt, 24 h, 70%.
a
Scheme 6. Short Synthesis to Calothrixins
a
Reagents and conditions: (i) AlCl3, (COCl)2, dry DCM, N2, 0 °C to rt, 3 h then aniline, K2CO3, dry THF, rt, overnight, 81%; (ii) 5 mol %
Pd(TFA)2, PhCOOH, O2, 120 °C, 24h, 83%; (iii) Tf2O, pyridine, dry DCM, −40 °C to rt, 2 h then Et3SiH, rt, 5 h, 87%.
(200 mL). The extract was washed with brine and dried over Na2SO4.
The solvent was removed, and the residue was purified by column
chromatography with hexanes/ethyl acetate (1:5) to give 4 (1.87 g,
82%). Yellow solid; mp 166−169 °C; IR (KBr) 3317, 2843, 2740,
1631 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.00 (br,
s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.34 (d, J =
7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.69 (d,
J = 8.4 Hz, 1H), 3.88 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
172.4, 155.4, 140.6, 138.8, 122.7, 122.3, 120.8, 119.5, 117.7, 117.5,
114.8, 109.4, 107.5, 55.6; HRMS (ESI-MS) m/z [M]+ calcd for
C14H11NO2 225.0790, found 225.0757.
In summary, we herein report the synthesis of calothrixin B
utilizing Pd-catalyzed intramolecular C−H/C−I and C−H/C−
H cross-coupling reactions that were used to construct the
indolophenanthridine system. For the first time, calothrixin-
related pentacycles 13−15 and 17 were prepared without any
substitution at the indole nitrogen. Also of particular note is the
fact that recourse to protection of the indole nitrogen atom was
unnecessary to achieve the pentacyclic ring of calothrixin B,
which was constructed with good overall yield of 27−35% and
also included the synthesis of calothrixin A.
Preparation of 4-Methoxy-9H-carbazole-3-carboxylic Acid
(5). To a solution of 4 (2.0 g, 8.8 mmol) in THF (20 mL) was added
30% aq H2O2 (3.0 mL, 88.7 mmol) dropwise under ice cooling. Then,
KH2PO4 (1.2 g, 8.8 mmol) in water (5 mL) followed by NaClO2 (1.59
g, 17.6 mmol) in water (5 mL) was added in a dropwise manner. The
reaction mixture was then raised to room temperature and stirred for 8
h. After completion of the reaction, the mixture was neutralized with
10% aq HCl and filtered. The solid obtained was recrystallized from
warm ethanol to yield 5 (2.06 g, 97%). Yellow solid, mp 183−186 °C;
IR (KBr) 3327, 2833, 2740, 1664 cm−1; 1H NMR (400 MHz, DMSO-
d6) δ 12.47 (s, 1H), 10.86 (br, s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.17
(d, J = 8.8 Hz, 1H), 7.60 (t, J = 8.4 Hz, 2H), 7.49 (t, J = 7.2 Hz, 1H),
7.33 (t, J = 7.6 Hz, 1H), 3.94 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) δ 171.3, 155.4, 140.6, 138.8, 122.7, 122.3, 120.8, 119.5, 117.7,
117.5, 114.8, 109.4, 107.5, 56.1; HRMS (ESI-MS) m/z [M]+ calcd for
C14H11NO3 241.0739, found 241.0716.
EXPERIMENTAL SECTION
■
General Information and Materials. The NMR experiments
were performed with 400 or 500 MHz spectrometer, and chemical
shifts are expressed in ppm (δ) with TMS as an internal reference. J
values are given in hertz. IR spectra were recorded by using KBr pellets
or neat. TOF and quadrupole mass analyzer types were used for the
HRMS measurements. Reactions were carried out under an inert
atmosphere (nitrogen) or oxygen and monitored by TLC. Column
chromatography was performed on silica gel (100−200 mesh) in glass
columns to purify the compounds. The solvents acetone, diethyl ether,
tetrahydrofuran (THF), methanol, chloroform, and dichloromethane
were dried by using standard distillation methods. Commercially
available reagents and solvents were used without further purification
and were purchased. Melting points were determined using open
capillary tubes and are uncorrected.
Preparation of N-(2-Iodophenyl)-4-methoxy-9H-carbazole-
3-carboxamide (6). A mixture of 5 (1 g, 4.1 mmol) and thionyl
chloride (1.5 mL, 20.4 mmol) in 20 mL of chloroform was heated at
reflux temperature for 6 h. Then, the residue was concentrated by the
aid of rotary evaporation. To a solution of the concentrated crude
product in THF (20 mL) K2CO3 (1.13 g, 8.2 mmol) and 2-iodoaniline
(1.34 g, 6.2 mmol) in THF (5 mL) were added. The mixture was then
Preparation of 4-Methoxy-9H-carbazole-3-carbaldehyde (4).
To a solution of 4-methoxy-9H-carbazole 3 (2 g, 10.9 mmol) and
NMF (2.0 mL, 16.4 mmol) in 1,2-dicholorobenzene (20 mL) was
added POCl3 (3.0 mL, 32.7 mmol) dropwise under ice cooling. Then,
the mixture was gradually raised to room temperature and stirred for 3
h at 70 °C. The mixture was then poured into ice and neutralized with
10% aqueous NaOH, and the residue was extracted with ethyl acetate
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Note
allowed to stir for 12 h at room temperature. After completion of the
reaction, the residue was extracted with ethyl acetate (100 mL),
washed with 10% aq HCl and brine, and dried over Na2SO4. The
solvent was removed, and the solid obtained was recrystallized from
methanol to afford 6 (1.63 g, 96%). Yellow solid, mp 176−179 °C; IR
CDCl3) δ 8.51 (d, J = 7.6 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.84−7.82
(dd, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H), 7.54−7.45 (m, 3H), 7.44−7.40 (m,
1H), 7.32−7.28 (dt, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H), 6.90−6.86 (dt, J1 =
1.6 Hz, J2 = 8.0 Hz, 1H), 5.91 (s, 2H), 5.81 (d, J = 10.4 Hz, 1H), 4.66
(d, J = 10.4 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 168.7, 152.4, 141.1, 139.6, 138.8, 134.6,
130.8, 129.3, 127.9, 127.5, 125.8, 125.6, 123.9, 123.2, 123.1, 121.8,
119.6, 117.4, 108.7, 82.4, 72.6, 57.8, 55.6, 53.7; HRMS (ESI-MS) m/z
calcd for C24H22N2O4 402.1580, found 401.1872 [M − 1]+, 402.1545
[M]+.
1
(KBr) 3320, 2850, 2735, 1673, 1448, 1104, 765 cm−1; H NMR (400
MHz, CDCl3) δ 8.50 (d, J = 7.5 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H),
7.93 (br, s, 1H), 7.84−7.81 (dd, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H), 7.54−
7.46 (m, 4H), 7.44−7.40 (m, 1H), 7.32−7.28 (m, 1H), 6.90−6.87 (m,
1H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 152.8,
141.1, 139.6, 138.8, 130.8, 129.3, 127.9, 127.5, 125.8, 125.6, 123.9,
123.2, 123.1, 121.8, 119.6, 108.7, 90.0, 55.8; HRMS (ESI-MS) m/z [M
− H]+ calcd for C20H15IN2O2 441.0100, found 441.0105.
7-Methoxy-5-(methoxymethyl)-5H-indolo[3,2-j]-
phenanthridin-6(12H)-one (13). Yield 74%; White solid, mp 269−
1
272 °C; IR (KBr) 3361, 1647 cm−1; H NMR (400 MHz, CDCl3) δ
10.11 (br, s, 1H), 8.51 (d, J = 7.6 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H),
7.84−7.82 (dd, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H), 7.54−7.50 (m, 1H),
7.48−7.44 (m, 2H), 7.42−7.40 (m, 1H), 7.32−7.26 (dt, J1 = 1.2 Hz, J2
= 6.8 Hz, 1H), 6.90−6.86 (dt, J1 = 1.6 Hz, J2 = 8.0 Hz, 1H), 5.81 (d, J
= 10.4 Hz, 1H), 4.66 (d, J = 10.4 Hz, 1H), 3.88 (s, 3H), 3.75 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 165.7, 151.6, 141.1, 139.6, 138.8,
134.6, 130.8, 129.3, 127.9, 127.5, 125.8, 125.6, 123.9, 123.2, 123.1,
121.8, 119.6, 117.4, 108.7, 74.2, 61.2, 56.4; HRMS (ESI-MS) m/z
[M]+ calcd for C22H18N2O3 358.1317, found 358.1316.
General Procedure for the Preparation of Compounds 10
and 14. To a solution of compound 9 or 13 (1 mmol) in dry Et2O
(10 mL) was added LAH (10 mmol) portionwise under ice-cold
condition with stirring. The reaction was gradually raised to room
temperature and stirred for 3 h. Then, 6 N HCl was added slowly to
the mixture under ice cooling, and the mixture was stirred for 30 min.
The precipitate formed was filtered, and the filtrate was washed with
Et2O (3 × 10 mL). The extracts were then washed with brine and
dried over Na2SO4. The solvent was removed on a rotary evaporator,
and the residue was recrystallized from methanol to yield the titled
compound.
Preparation of N-(2-Iodophenyl)-4-methoxy-N,9-bis-
(methoxymethyl)-9H-carbazole-3-carboxamide (7). To a sus-
pension of NaH (60% dispersion in oil, 236 mg, 9.8 mmol) in dry
THF (20 mL) under ice cooling was added a solution of 6 (500 mg,
1.1 mmol) in dry THF (10 mL) slowly followed by freshly prepared
chloro(methoxy)methane (1.5 mL, 19.3 mmol) under nitrogen
atmosphere, and the mixture was stirred for 30 min. The mixture
was gradually raised to room temperature and heated to 50 °C for 20
h. The mixture was concentrated on rotary evaporator, the residue was
extracted with ethyl acetate (100 mL), and the extract was washed with
brine and dried over Na2SO4. The solvent was removed, and the
residue was recrystallized from methanol to give 7 (0.55 g, 92%).
Yellow solid, mp 248−251 °C; IR (KBr) 2891, 2387, 1641, 1221, 1109
1
cm−1; H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 7.6 Hz, 1H), 8.30
(d, J = 8.0 Hz, 1H), 7.84−7.82 (dd, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H),
7.54−7.50 (m, 4H), 7.48−7.40 (m, 1H), 7.32−7.26 (m, 1H), 6.90−
6.86 (m, 1H), 5.94 (s, 2H), 5.81 (d, J = 9.2 Hz, 1H), 4.86 (d, J = 6.4
Hz, 1H), 3.84 (s, 3H), 3.75 (s, 3H), 3.72 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 168.7, 151.9, 141.1, 139.6, 138.8, 130.8, 129.3, 127.9,
127.5, 125.8, 125.6, 123.9, 123.2, 123.1, 121.8, 119.6, 108.7, 90.0, 76.1,
73.1, 56.7, 56.3, 55.8; HRMS (ESI-MS) m/z [M]+ calcd for
C24H23IN2O4 530.0703, found 530.0710.
7-Methoxy-12-(methoxymethyl)-12H-indolo[3,2-j]-
phenanthridine (10). Yield 87%; light orange solid, mp 267−269
1
°C; IR (KBr) 2764, 2334, 1349, 1151 cm−1; H NMR (400 MHz,
Preparation of N-(2-Iodophenyl)-4-methoxy-N-(methoxy-
methyl)-9H-carbazole-3-carboxamide (8). To a solution of 6
(500 mg, 1.1 mmol) in dry CHCl3 (20 mL) was added P2O5 (0.96 g,
3.3 mmol) under nitrogen atmosphere. Then, dimethoxymethane (1
mL, 11.3 mmol) was added in a dropwise manner. The reaction
mixture was allowed warm to room temperature and stirred for 8 h.
After completion of the reaction, the solvent was removed, and the
residue obtained was quenched with 10% aq Na2CO3 (100 mL) and
then extracted with ethyl acetate (200 mL). The extract was
concentrated and purified by silica gel column chromatography with
hexanes/ethyl acetate (7:3) to give 8 (0.48 g, 89%). Yellow solid, mp
CDCl3) δ 8.52 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.84−7.82 (dd, J1 =
1.6 Hz, J2 = 8.0 Hz, 1H), 7.93 (s, 1H), 7.54−7.50 (m, 3H), 7.48−7.40
(m, 1H), 7.32−7.26 (m, 1H), 6.90−6.86 (dt, J1 = 1.2 Hz, J2 = 8.0 Hz,
1H), 5.85 (s, 2H), 3.81 (s, 3H), 3.78 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 153.1, 148.3, 141.1, 139.6, 138.8, 130.8, 129.3, 127.9, 127.5,
125.8, 125.6, 123.9, 123.2, 123.1, 121.8, 119.6, 117.4, 108.7, 74.1, 61.1,
55.5; HRMS (ESI-MS) m/z [M]+ calcd for C22H18N2O2 342.1368,
found 342.1348.
7-Methoxy-12H-indolo[3,2-j]phenanthridine (14). Yield 94%;
1
light yellow oil; IR (neat) 3421, 3365, 2786, 1320, 1167 cm−1; H
1
231−234 °C; IR (KBr) 3389, 2745, 1651, 1192, 743 cm−1; H NMR
NMR (400 MHz, CDCl3) δ 10.04 (br, s, 1H), 8.50 (s, 1H), 8.30 (d, J
= 8.0 Hz, 1H), 7.84−7.82 (dd, J1 = 1.2 Hz, J2 = 8.0 Hz, 2H), 7.54−
7.50 (m, 3H), 7.48−7.40 (m, 1H), 7.32−7.26 (dt, J1 = 1.2 Hz, J2 = 6.8
Hz, 1H), 6.90−6.86 (dt, J1 = 1.6 Hz, J2 = 8.0 Hz, 1H), 3.85 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 152.2, 148.1, 141.1, 139.6, 138.8,
130.8, 129.3, 127.9, 127.5, 125.8, 125.6, 123.9, 123.2, 123.1, 121.8,
119.6, 117.4, 108.7, 57.7; HRMS (ESI-MS) m/z [M]+ calcd for
C20H14N2O 298.1106, found 298.1112.
General Procedure for the Preparation of Compounds 11
and 15. A 25-mL oven-dried, round-bottom flask was charged with 1
mmol of 10 or 14. The flask was purged with nitrogen and sealed with
a rubber septum. With oven-dried syringes, 10 mL of sulfolane,
pyridine (0.5 mL, 0.06 mmol), and freshly prepared iodotrimethylsi-
lane (3.5 mL, 24 mmol) were injected into the flask in the order
specified. When the iodotrimethylsilane is added, the solution becomes
slightly yellow and a precipitate appears. The mixture was heated with
stirring at 70° for 20 h, after which the reaction was normally
complete. Anhydrous methanol (5 mL) was added, the mixture was
cooled to room temperature, and the volatile components were
removed on a rotary evaporator. Approximately 20 mL of anhydrous
diethyl ether was added, and the resulting suspension was filtered,
removing pyridinium hydro iodide. The flask and the filter cake were
washed thoroughly with 50 mL of anhydrous ether. The solvent was
evaporated, and the residual oil was purified by chromatography on
(400 MHz, CDCl3) δ 8.51 (d, J = 7.6 Hz, 1H), 8.30 (d, J = 8.0 Hz,
1H), 7.93 (br, s, 1H), 7.84−7.82 (dd, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H),
7.54−7.50 (m, 3H), 7.44−7.40 (m, 2H), 7.32−7.26 (m, 1H), 6.90−
6.86 (m, 1H), 6.53 (d, J = 6.4 Hz, 1H), 5.81 (d, J = 9.2 Hz, 1H), 3.83
(s, 3H), 3.59 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 151.9,
141.1, 139.6, 138.8, 130.8, 129.3, 127.9, 127.5, 125.8, 125.6, 123.9,
123.2, 123.1, 121.8, 119.6, 108.7, 90.0, 77.7, 56.7, 55.8; HRMS (ESI-
MS) m/z [M]+ calcd for C22H19IN2O3 486.0440, found 486.0442.
General Procedure for the Synthesis of Compounds 9 and
13. An oven-dried Ace Pressure tube was charged with Pd(OAc)2 (5
mol %), Ag2O (10 mol %), appropriate compound 7 or 8 (1 mmol),
KOAc (2 mmol) [ in case of 8, 3 mmol of base used], and DMF (5
mL) and then capped with a Teflon screw cap, and the mixture was
heated to 110 °C with stirring for appropriate time. After completion
of the reaction, the mixture was cooled to room temperature and
diluted with water, and the residue was extracted with ethyl acetate.
The extract was then washed with 10% aq NH4Cl and brine and dried
over Na2SO4. The solvent was removed; the resulting residue was
purified by silica gel column chromatography on hexanes/ethyl acetate
(7:3) to afford the titled compound.
7-Methoxy-5,12-bis(methoxymethyl)-5H-indolo[3,2-j]-
phenanthridin-6(12H)-one (9). Yield 81%; white solid; mp 274−
277 °C; IR (KBr) 2874, 2598, 1664, 1452 cm−1; 1H NMR (400 MHz,
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Note
silica gel packed with anhydrous ether in a glass column. The column
was eluted with anhydrous ether, and 10−15 mL fractions were
collected and analyzed by TLC. Fractions containing product were
combined and evaporated, affording title compound.
12-(Methoxymethyl)-12H-indolo[3,2-j]phenanthridin-7-ol
(11). Yield 76%; orange oil; IR (neat) 3382, 2576, 2471, 1451, 1194
cm−1; 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.43 (s, 1H),
7.82 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.22−
7.20 (m, 2H), 7.06 (t, J = 8.4 Hz, 1H), 7.02 (t, J = 10.4 Hz, 1H), 6.94−
6.90 (m, 1H), 6.85−6.82 (m, 1H), 5.72 (s, 2H), 3.78 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 150.6, 148.5, 140.8, 139.8, 131.1,
128.4, 126.4, 122.8, 122.0, 120.2, 119.6, 119.0, 117.7, 117.1, 113.6,
111.9, 108.5, 107.5, 105.5, 70.4, 53.3; HRMS (ESI-MS) m/z [M + H]+
calcd for C21H16N2O2 328.1291, found 329.1314.
12H-Indolo[3,2-j]phenanthridin-7-ol (15). Yield 86%; thick
orange liquid; IR (neat) 3402, 3386, 2845, 1441, 1197 cm−1; 1H
NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.86 (br, s, 1H), 8.41
(s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.62−7.57
(m, 2H), 7.50 (t, J = 10.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.32 (t, J
= 7.6 Hz, 1H), 7.24−7.20 (m, 1H), 6.90−6.86 (m, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 150.8, 148.5, 140.8, 139.8, 133.4, 131.1,
128.4, 126.4, 122.8, 122.0, 120.2, 119.6, 119.0, 117.7, 117.1, 113.6,
111.9, 108.5, 107.5; HRMS (ESI-MS) m/z calcd for C19H12N2O
284.0950, found 284.1072 [M]+, 285.1082 [M + 1]+.
Preparation of 12-(Methoxymethyl)-7H-indolo[3,2-j]-
phenanthridine-7,13(12H)-dione (12). Phenol 11 (20 mg, 0.060
mmol) in a 5:1 mixture of acetone/5% aq NaOH (5 mL) was stirred at
room temperature under O2 for 18 h. The mixture was concentrated,
water (5 mL) was added, and the precipitate formed was collected by
filtration and recrystallized from ethanol to give 12 (18 mg, 88%).
Orange solid; mp 230−232 °C (lit.5 mp 234−235 °C); IR (KBr)
2921, 2853, 1650 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.79 (s, 1H),
9.62 (d, J = 8.8 Hz, 1H), 8.41 (d, J = 8.2 Hz, 1H), 8.20 (d, J = 8.1 Hz,
1H), 7.86−7.78 (m, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.56−7.53 (m,
1H), 7.44−7.40 (m, 1H), 5.83 (s, 2H), 3.84 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 180.4, 179.6, 152.3, 148.1, 135.6, 133.1, 131.7, 131.5,
130.5, 130.3, 128.4, 127.6, 125.5, 124.5, 123.8, 123.1, 119.6, 113.3,
76.1, 56.3; HRMS (ESI-MS) m/z [M + H]+ calcd for C21H14N2O3
343.1083, found 343.1080.
aqueous Na2CO3 to remove benzoic acid. The aqueous layer was
extracted with AcOEt (three times). The combined organic layer was
washed with water and brine, dried over Na2SO4, and concentrated to
give crude, in which benzoic acid was not contained. The residue was
purified by column chromatography on silica gel on hexanes/ethyl
acetate (7:3) to afford 17 as a light yellow solid (0.41 g, 83%).
7-Methoxy-5H-indolo[3,2-j]phenanthridin-6(12H)-one (17).
Pale yellow solid; mp 246−248 °C; IR (KBr) 3341, 2871, 1609,
1204 cm−1; 1H NMR (CDCl3+DMSO-d6, 400 MHz) δ 10.93 (s, 1H),
9.97 (s, 1H), 7.99 (s, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.49 (d, J = 8.8
Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.00 (t, J =
7.2 Hz, 1H), 6.69−6.65 (m, 2H), 6.38 (d, J = 8.8 Hz, 1H), 3.85 (s,
3H); 13C NMR CDCl3+DMSO-d6, 100 MHz) δ 172.6, 156.7, 140.1,
139.5, 134.0, 130.8, 128.8, 124.6, 124.2, 123.1, 122.4, 122.2, 120.6,
118.8, 116.1, 115.8, 108.0, 107.4, 53.8; HRMS (ESI-MS) m/z [M −
H]+ calcd for C20H14N2O2 314.1055, found 313.0935.
Calothrixin B (2). Ferric chloride (8 mg, 0.05 mmol) was added by
portions to a mixture of 15 (30 mg, 0.1 mmol), 70% aq TBHP (0.1
mL, 1 mmol), and 2,6-dicarboxy pyridine-1-oxide (2 mg, 0.01 mmol)
in tert-amyl alcohol (2 mL) under ice cooling. Then, the mixture was
gradually raised to room temperature and stirred for 8 h. The mixture
was diluted with CH2Cl2 (50 mL), washed with brine, and dried over
Na2SO4. The solvent was removed, and the residue obtained was
purified by silica gel column chromatography on hexanes/ethyl acetate
(5:1) to give 2 (18 mg, 71%). Red solid; mp 296−299 °C (lit.1 mp
1
≥300 °C); IR (KBr) 3389, 1651 cm−1; H NMR (500 MHz, DMSO-
d6) δ 12.84 (br s, 1H), 9.60 (s, 1H), 9.55 (d, J = 8.2 Hz, 1H), 8.18 (d, J
= 7.6 Hz, 1H), 8.14 (t, J = 8.4 Hz, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.83
(t, J = 8.8 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 6.6 Hz, 1H),
7.34 (t, J = 7.8 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 181.0,
180.7, 151.7, 148.0, 133.1, 132.1, 130.7, 130.3, 127.7, 127.6, 125.5,
124.8, 123.9, 123.1, 122.8, 116.2, 114.8; HRMS (ESI-MS) m/z calcd
for C19H10N2O2 298.0821; found 298.1036 [M]+, 299.0872 [M + H]+.
Calothrixin A (1). A mixture of benzonitrile (9 mg, 0.08 mmol),
70% aq TBHP (0.2 mL), and NaOH (5 mg, 0.1 mmol) in acetone (2
mL) was cooled to 0 °C. Charge calothrixin B 2 (10 mg, 0.03 mmol)
in acetone (1 mL) was added dropwise. The reaction mixture was
stirred at room temperature for 24 h and then poured into saturated
aqueous sodium hydrogen carbonate (10 mL). The mixture was
extracted with dichloromethane (3 × 15 mL), the combined organic
phases were dried over Na2SO4, and the solvent was evaporated. The
crude material was subjected to column chromatography, eluting with
dichloromethane containing triethylamine (1% v/v), to give the title
compound 1 (7 mg, 70%). Red solid; mp 286−288 °C (lit.1 mp ≥280
Synthesis of 4-Methoxy-N-phenyl-9H-carbazole-3-carboxa-
mide (16). To a solution of 4-methoxycarbazole 3 (1 g, 5.1 mmol) in
dry DCM (20 mL) was added AlCl3 (1.02 g, 7.65 mmol) in a two neck
round-bottom flask, which was purged with nitrogen and sealed with a
rubber septum. The contents were stirred at room temperature for 30
min. Then, oxalyl chloride (0.95 mL, 10.1 mmol) was added slowly to
the mixture at 0 °C and stirred for 30 min. The mixture was then
brought back to room temperature for a further 3 h of stirring. The
solid residue was filtered off, and the filtrate was directly added to a
MeOH solution containing aniline (0.42 mL, 4.63 mmol) and K2CO3
(1 g, 7.72 mmol) in a dropwise manner. The whole contents were
stirred at room temperature overnight. After the completion of the
reaction, the mixture was poured into 10% aq HCl (60 mL) and
extracted with ethyl acetate (3 × 40 mL). The solvent was removed;
the solid obtained was washed with hot ether (5 × 30 mL) gave 16
(1.4 g, 81%). Yellow solid; mp 209−211 °C; IR (KBr) 3369, 2945,
1
°C); IR (KBr) 3340, 1671 cm−1; H NMR (500 MHz, DMSO-d6) δ
12.89 (br s, 1H), 9.64 (d, J = 6.7 Hz, 1H), 8.85 (s, 1H), 8.58 (d, J = 6.8
Hz, 1H), 8.10 (d, J = 7.0 Hz, 1H), 7.94 (t, J = 8.3 Hz, 1H), 7.91 (t, J =
5.5 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.41 (t, J = 6.6 Hz, 1H), 7.35 (t,
J = 9.9 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 178.8, 178.3,
143.7, 139.2, 138.8, 132.5, 132.3, 130.5, 128.7, 127.6, 127.4, 125.0,
124.1, 122.6, 122.5, 119.5, 115.7, 114.8; HRMS (ESI-MS) m/z [M +
H]+ calcd for C19H10N2O3 315.0770, found 315.0774.
1
2426, 1643, 1198, 1046 cm−1; H NMR (CDCl3 + DMSO-d6, 400
ASSOCIATED CONTENT
MHz) δ 11.04 (s, 1H), 10.04 (s, 1H), 7.81−7.76 (m, 2H), 7.58 (d, J =
8.4 Hz, 1H), 7.32−7.30 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 6.96 (t, J =
7.6 Hz, 1H), 6.91 (t, J = 8.0 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 6.74 (t,
J = 7.6 Hz, 1H), 6.27−6.22 (m, 1H), 3.67 (s, 3H); 13C NMR
CDCl3+DMSO-d6, 100 MHz) δ 192.7, 158.5, 140.2, 137.7, 132.2,
129.0, 124.4, 124.0, 121.49, 121.45, 120.4, 119.9, 119.3, 118.5, 111.6,
110.8, 109.9, 54.6; HRMS (ESI-MS) m/z [M − H]+ calcd for
C20H16N2O2 315.1133, found 315.1112.
Typical Procedure for Pd-Catalyzed Oxidative Coupling
Reaction of 16. To a Schlenk tube were added Pd(OCOCF3)2 (35
mg, 0.079 mmol), 16 (0.5 g, 1.58 mmol), and benzoic acid (5.0 g).
The Schlenk tube was flushed and maintained with O2, and then the
reaction mixture was stirred at 120 °C for 24 h. After cooling to room
temperature, the mixture was dissolved in AcOEt and neutralized with
■
S
* Supporting Information
Complete characterization data (1H NMR, 13C NMR, and mass
spectra) for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rnsc@uohyd.ernet.in.
Notes
The authors declare no competing financial interest.
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The Journal of Organic Chemistry
Note
T.; Akiyama, T.; Abe, H.; Takeuchi, Y. J. Chem. Soc., Perkin Trans. 1
2001, 523−528.
(10) (a) Olah, G. A; Narang, S. C. Tetrahedron 1982, 38, 2225−2227.
(b) Ho, T.-L.; Olah, G. A. Angew. Chem., Int. Ed. Engl. 1976, 15, 774−
775. (c) Ho, T.-L.; Olah, G. A. Synthesis 1977, 417−418.
(11) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004,
ACKNOWLEDGMENTS
■
We gratefully acknowledge DST for financial support (Project
No SR/S1/OC-70/2008). N.R. thanks CSIR, New Delhi for
research fellowship and contingency grant. N.R. dedicates this
paper to his school teacher Parvathi Madam.
104, 6217−6254. (b) Mooller, K.; Wienhoofer, G.; Schrooder, K.;
̈
̈
̈
Join, B.; Junge, K.; Beller, M. Chem.Eur. J. 2010, 16, 10300−10303.
(c) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293−1314.
(12) (a) Asche, C.; Frank, W.; Albert, A.; Kucklaender, U. Bioorg.
Med. Chem. 2005, 13, 819−837. (b) Tao, Z.-F.; Sowin, T. J.; Lin, N.-H.
Tetrahedron Lett. 2005, 46, 7615−7618.
DEDICATION
■
This work is dedicated to Prof. P. C. Srinivasan, Department of
Organic Chemistry, University of Madras, Chennai, India for
his contribution toward carbazole chemistry.
(13) (a) Katritzky, A. R.; Lagowski, J. M. Chemistry of the Heterocyclic
N-Oxides; Academic Press: London, 1971. (b) Rousseau, R. J.; Robins,
R. K. J. Heterocycl. Chem. 1965, 2, 196−201. (c) Katritzky, A. R.; Lam,
J. N. Heterocycles 1992, 33, 1011−1049.
(14) (a) Hanada, S.; Tsutsumi, E.; Motoyama, Y.; H. Nagashima, H.
J. Am. Chem. Soc. 2009, 131, 15032−15040. (b) Das, S.; Addis, D.;
Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2010, 132, 1770−
1771. (c) Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am. Chem. Soc.
2010, 132, 12817−12819.
REFERENCES
■
(1) Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; de Chazal, N. M.;
Kirk, J.; Kirk, K.; Saliba, K. J.; Smith, G. D. Tetrahedron 1999, 55,
13513−13520.
(2) (a) Matsumoto, K.; Choshi, T.; Hourai, M.; Zamami, Y.; Sasaki,
K.; Abe, T.; Ishikura, M.; Hatae, N.; Iwamura, N.; Tohyama, S.;
Nobuhiro, J.; Hibino, S. Bioorg. Med. Chem. Lett. 2012, 22, 4762−4764.
(b) Bernardo, P. H.; Chai, C. L. L.; Heath, G. A.; Mahon, P. J.; Smith,
G. D.; Waring, P.; Wilkes, B. A. J. Med. Chem. 2004, 47, 4958−4963.
(c) Khan, Q. A.; Lu, J.; Hecht, S. M. J. Nat. Prod. 2009, 72, 438−442.
(3) Kelly, T. R.; Zhao, Y.; Cavero, M.; Torneiro, M. Org. Lett. 2000,
2, 3735−3737.
NOTE ADDED AFTER ASAP PUBLICATION
Figure 1 and Schemes 3 and 5 were corrected on March 15,
2013.
■
(4) (a) Choshi, T.; Hibino, S. Heterocycles 2009, 77, 85−97.
(b) Tohyama, S.; Choshi, T.; Matsumoto, K.; Yamabuki, A.; Hieda, Y.;
Nobuhiro, J.; Hibino, S. Heterocycles 2010, 82, 397−416. (c) Abe, T.;
Ikeda, T.; Yanada, R.; Ishikura, M. Org. Lett. 2011, 13, 3356−3359.
(d) Bhosale, S. M.; Gawade, R. L.; Puranik, V. G.; Kusurkar, R. S.
Tetrahedron Lett. 2012, 53, 2894−2896. (e) Bennasar, M. -L.; Roca, T.;
Ferrando, F. Org. Lett. 2006, 8, 561−564. (f) Bernardo, P. H.; Chai, C.
L. L. J. Org. Chem. 2003, 68, 8906−8909. (g) Bernardo, P. H.; Chai, C.
L. L.; Elix, J. A. Tetrahedron Lett. 2002, 43, 2939−2940. (h) Sissouma,
D.; Maingot, L.; Collet, S.; Guingant, A. J. Org. Chem. 2006, 71, 8384−
8389. (i) Tohyama, S.; Choshi, T.; Matsumoto, K.; Yamabuki, A.;
Ikegata, K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2005, 46, 5263−
5264.
(5) (a) McErlean, C. S. P.; Sperry, J.; Blake, A. J.; Moody, C. J.
Tetrahedron 2007, 63, 10963−10970. (b) Yamabuki, A.; Fujinawa, H.;
Choshi, T.; Tohyama, S.; Matsumoto, K.; Ohnuma, K.; Nobuhiro, J.;
Hibino, S. Tetrahedron Lett. 2006, 47, 5859−5861. (c) Sperry, J.;
McErlean, C. S. P.; Slawin, A. M. Z.; Moody, C. J. Tetrahedron Lett.
2007, 48, 231−234.
(6) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; deMeijere,
A.; Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (b) Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
Wiley Interscience: New York, 2002.
(7) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147−
1169. (b) Díaz-Requejo, M. M.; Per
́
ez, P. J. Chem. Rev. 2008, 108,
3379−3394. (c) Schmidt, A. W.; Reddy, K. R.; Knolker, H.-J. Chem.
̈
Rev. 2012, 112, 3193−3328. (d) Ritleng, V.; Sirlin, C.; Pfeffer, M.
́
Chem. Rev. 2002, 102, 1731−1770. (e) Díaz-Requejo, M. M.; Perez, P.
J. Chem. Rev. 2008, 108, 3379−3394. (f) Knolker, H.-J. Chem. Lett.
̈
2009, 38, 8−13. (g) Knolker, H.-J.; Reddy, K. R. In The Alkaloids;
̈
Cordell, G. A., Ed.; Academic Press: Amsterdam, 2008; Vol. 65, p 1.
(h) Bauer, I.; Knolker, H.-J. Top. Curr. Chem. 2012, 309, 203−253.
̈
́
(8) (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359−1469. (b) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442−4489. (c) Pulido, F.
J.; Barbero, A.; García, C. Tetrahedron 2009, 65, 5535−5540.
(d) Bowie, A. L.; Trauner, D. J. Org. Chem. 2009, 74, 1581−1586.
(e) Frye, E. C.; O’Connor, C. J.; Twigg, D. G.; Elbert, B.; Laraia, L.;
Hulcoop, D. G.; Venkitaraman, A. R.; Spring, D. R. Chem.Eur. J.
2012, 18, 8774−8779.
(9) (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111,
1417−1492. (b) Weibel, J.-M.; Blanc, A.; Pale, P. Chem. Rev. 2008,
108, 3149−3173. (c) Shi, W.; Liu, C.; Lei, A. Chem. Soc. Rev. 2011, 40,
2761−2776. (d) Harayama, T.; Akamatsu, H.; Okamura, K.; Miyagoe,
2807
dx.doi.org/10.1021/jo302821v | J. Org. Chem. 2013, 78, 2802−2807