Total synthesis of carbazomycin G

Article abstract of DOI:10.1002/ejoc.201300467

A concise total synthesis of carbazomycin G has been completed in five steps. Cerium(IV) ammonium nitrate (CAN)-SiO₂-mediated oxidation of 2-methyl-2,3,4,9-tetrahydro-1H- carbazol-1-one afforded a carbazole-1,4-quinone derivative, 2-methyl-1H-c

Full text of DOI:10.1002/ejoc.201300467

FULL PAPER
DOI: 10.1002/ejoc.201300467
Total Synthesis of Carbazomycin G
Suchandra Chakraborty[a] and Chandan Saha*[a]
Keywords: Medicinal chemistry / Antibiotics / Total synthesis / Alkaloids / Cerium / Oxidation / Quinones
A concise total synthesis of carbazomycin G has been com- developed HBF4 catalysis conditions, yielded 4-hydroxy-2-
pleted in five steps. Cerium(IV) ammonium nitrate (CAN)–
SiO2-mediated oxidation of 2-methyl-2,3,4,9-tetrahydro-1H-
carbazol-1-one afforded a carbazole-1,4-quinone derivative,
methyl-9H-carbazole-1,3-diyl diacetate. Finally, CAN-SiO2-
mediated oxidative hydrolysis of the acetylation product and
O-methylation using a stoichiometric amount of diazometh-
2-methyl-1H-carbazole-1,4(9H)-dione, the synthetic pre- ane and subsequent regioselective nucleophilic addition of
cusor, which on, which, on Thiele acetylation under newly
methyllithium led to carbazomycin G.
Introduction
The carbazomycins A–F, a new group of antibiotics, were
first isolated from Streptoverticillium ehimense H 1051-MY
10 by Nakamura and his group (Figure 1).[1] Nakamura et
al. also isolated carbazomycins G and H (Figure 1) pos-
sessing a unique quinol moiety from the same microorga-
nism.[1f] This group described the structure elucidation and
biogenesis of carbazomycins, and pointed out that the bio-
genesis of carbazomycins, which are derived from trypto-
phan, was unlike that of carbazole alkaloids isolated from
terrestrial plants.[1d] These carbazomycin alkaloids have
promising biological activities including the antifungal ac-
tivity[2] against Trichophyton species by carbazomycin G.
Although carbazomycin G has a stereogenic centre at C-1,
the compound elicits no optical rotation, which leads to the
conclusion that carbazomycin G is a racemate in nature.[2]
The complex substitution pattern of all these carbazomy-
cins means that these naturally occurring compounds are
a challenging synthetic target. Nevertheless, the promising
biological activities of carbazomycins led to the develop-
ment of the total syntheses of this class of compounds by
several groups.[3] Knölker et al.[4,5] communicated the first
iron-mediated total synthesis of carbazomycin G and H.
They constructed the carbazole framework by means of
consecutive C–C and C–N bond formation using tricarbon-
yliron complexed cyclohexadienylium cations and suitably
substituted aromatic amine. The same group also synthe-
sised carbazomycin G and H in the following year by using
an alternative, convergent route to carbazoles utilising pal-
ladium-catalysed[6] cyclisation of N,N-diarylamines. A third
Figure 1. Naturally occurring carbazomycins.
total synthesis of carbazomycin G, through an allene-medi-
ated electrocyclic reaction starting from 3-vinylindole, was
reported more recently by Hibino and co-workers.[7] Re-
cently, a synthetic methodology for the synthesis of carb-
azoloquinones through single-step oxidation with cerium-
(IV) ammonium nitrate (CAN) from keto-tetrahydrocarb-
azoles was developed in our laboratory.[8] Here, we commu-
nicate the total synthesis of carbazomycin G, employing
this methodology of quinone preparation as a key step.
Retrosynthetic Plan
Retrosynthetic analysis of carbazomycin G (7), with the
unique quinol moiety, led us to carbazole-1,4-quinone 9,
which was originally introduced as a precursor for carbazo-
mycin G in 1997 by Knölker et al.[4] (Scheme 1). Franzblau
and Knölker described the significant anti-TB activity of
9[9] and, in 2011, Lumyong et al. isolated this compound
from natural sources.[10,3c] Because CAN-SiO2-mediated
[a] Department of Clinical and Experimental Pharmacology,
School of Tropical Medicine,
C. R. Avenue, Kolkata 700073, India
E-mail: katichandan@yahoo.co.in
Homepage: www.stmkolkata.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300467.
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S. Chakraborty, C. Saha
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Scheme 1. Retrosynthetic pathway for carbazomycin G.
oxidation[8] of 2-methyl-2,3,4,9-tetrahydro-1H-carbazol-1- NMR studies), which, on condensation with phenyldiazon-
one (14) leads to 13, our attention was drawn towards the ium chloride (17) under Japp–Klingemann conditions,[12]
accessibility of 9 through hydrolysis of the acetoxy group furnished 2-methyl-6-(2-phenylhydrazono)cyclohexanone
of quinone 11 and subsequent O-methylation. The required (18). The required compound 14 was obtained through Fi-
2-methyl-1,4-dioxo-4,9-dihydro-1H-carbazol-3-yl
acetate scher indole cyclisation[12] of 18 by heating to reflux in gla-
(11) can be synthesised from carbazoloquinone 13 through cial acetic acid in the presence of concentrated hydrochloric
Thiele acetylation followed by oxidation of intermediate 12. acid for 3 min. CAN-SiO2-mediated oxidation[8] of 14 at
To obtain quinone 13, the key intermediate, required access room temperature afforded the expected quinone 13 in 58%
to 2-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (14), yield (Scheme 2). The first synthesis of carbazolequinone 13
which can be synthesised through Fischer indole cyclization was described by Knölker et al. using an approach involv-
of substituted cyclohexane-1,2-dione-1-phenylhydrazone ing palladium-catalysis .[13]
formed by the Japp–Klingemann procedure from phenyldi-
azonium chloride and suitably substituted 1,3-dicarbonyl
compound.
Synthesis of Carbazomycin G
Because we required quinone 9 as a precursor for the
Synthesis of Key Intermediate 2-Methyl-1H-carbazole-
synthesis of carbazomycin G, Thiele acetylation was carried
1,4(9H)-dione (13)
out on 13 under milder conditions using HBF4 as catalyst
The synthesis of 14 was initiated from commercially at 65–70 °C. Such treatment afforded 4-hydroxy-2-methyl-
available 2-methylcyclohexanone (15; Scheme 2). Claisen 9H-carbazole-1,3-diyl diacetate (19) instead of 12
condensation[11] on 15 with ethyl formate using metallic so- (Scheme 3). The spectroscopic data (1H and 13C NMR) of
dium in anhydrous ether in the presence of one drop of 19 suggested the presence of two acetyl groups instead of
ethanol afforded 3-methyl-2-oxocyclohexanecarbaldehyde three. In addition, the structure of 19 was supported by the
(16, which exists in two tautomeric forms as evident from mechanistic rationale[14] of Thiele acetylation.
Scheme 2. Synthesis of 2-methyl-1H-carbazole-1,4(9H)-dione (13).
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Total Synthesis of Carbazomycin G
Scheme 3. Synthesis of carbazomycin G.
In practice, Thiele acetylation on 13 under usual conc. Table 1. Screening of acid catalysts for the Thiele acetylation of 13.
H2SO4 conditions[15] proved to be unsuccessful in our
Entry
Catalyst
Temp.
[°C]
Time Yield
hands, resulting in the formation of a tarry mass together
with a small amount of 19 (26%). This important Thiele
acetylation was then studied under several acid catalysis
conditions (Table 1). It was found that the use of HBF4 as
catalyst afforded significantly higher yields of 19. Under the
optimised conditions, 19 was obtained in 51% yield, which
is, to the best of our knowledge, the first report of Thiele
acetylation performed under HBF4 catalysis conditions.
Compound 19, on further solid-phase CAN-SiO2-medi-
[h]
(%)
1
2
3
4
5
6
7
Conc. H2SO4
Conc. H2SO4
90–100
60–70
5
5
4
26
14
0
BF3·AcOH (ca. 40% soln.)[16] r.t.
60% HClO4
r.t.
4
2.5
5
10
36
51
45
48% HBF4 soln.
48% HBF4 soln.
48% HBF4 soln.
65–70
65–70
65–70
7
ated oxidation,[8] afforded 3-hydroxy-2-methyl-1H-carb- is dominated by radical and radical cation chemistry,[17,18]
azole-1,4(9H)-dione (10) in 67% yield through oxidation and the fate of these reactive intermediates determines the
with concomitant hydrolysis of the C-3 acetoxy group. The nature of the organic oxidation products. Thus, the key step
chemistry of CeIV-mediated oxidations of organic molecules for oxidation of 19 was anticipated to be N-hydroxylation,
Scheme 4. Plausible mechanistic rationale for the conversion of 19 into 10 under CAN-SiO2 conditions.
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which has been documented.[8] CeIV may participate in the
process by forming a complex[8,19] as shown in Scheme 4,
which ultimately leads to the hydrolysis of the C-1 acetoxy
group. Subsequently, cleavage of the N–O bond is aided by
the acetoxy group at C-3, followed by concomitant hydroly-
sis[20] of the acetoxy group, which ultimately leads to the
formation of 10. The latter is the 3-hydroxy-derivative of 13
and is obtained without recourse to hydrolysis of 11, which
was the proposed synthetic intermediate in the retrosyn-
thetic analysis presented in Scheme 1.
Compound 10, on methylation using excess diazometh-
ane, yielded the N-methylated derivative of carbazomy-
cin G, i.e., 3-methoxy-2,9-dimethyl-1H-carbazole-1,4(9H)-
dione (20). Thus, methylation[21] of 10 was carried out using
a stoichiometric amount of diazomethane to furnish the
(50 mL) and the combined aqueous extracts were washed with di-
ethyl ether (50 mL). The aqueous layer was acidified with 6 n hy-
drochloric acid (8.0 mL) and extracted with diethyl ether (2ϫ
80 mL). The organic layer was extracted and washed with brine
and then dried with anhydrous sodium sulfate. The organic layer,
on evaporation followed by vacuum distillation (70 °C/0.5 Torr),
gave product 16 (10 g, 70% yield) as a colourless oil. 1H NMR
(CDCl3, 500 MHz): δ = 1.21 (d, J = 7.0 Hz, 3 H, CH3), 1.37–1.42
(m, 1 H), 1.57–1.60 (m, 1 H), 1.76–1.80 (m, 1 H), 1.85–1.89 (m, 1
H), 2.32–2.35 (m, 2 H), 2.45–2.49 (m, 1 H), 8.60 (s, 1 H, CHO),
14.55 (br. s, 1 H, enol-OH) ppm. 13C NMR and DEPT (125 MHz,
CDCl3): δ = 17.47 (CH3), 20.99 (CH2), 23.77 (CH2), 30.03 (CH2),
35.86 (CH), 108.31 (CH), 187.00 (C), 188.62 (C) ppm. HRMS (Q-
TOF): m/z calcd. for C8H13O2 [M + H]+ 141.0912; found 141.0917.
2-Methyl-6-(2-phenylhydrazono)cyclohexanone (18): An aqueous
solution of sodium acetate trihydrate (20 g) in water (80 mL) was
precursor of carbazomycin G, quinone 9, in 95% yield. It added to a solution of 16 (14 g, 0.1 mol) in methanol (160 mL)
cooled to 0 °C, then a solution of phenyldiazonium chloride (pre-
pared from 0.1 mol aniline) was added dropwise with stirring. The
yellow solid compound 18, thus obtained, was collected by fil-
tration and washed with water. Upon crystallization from aqueous
methanol, 18 (18.5 g, yield 86%) was obtained as yellow crystals;
m.p. 98 °C (ref.[22] 97 °C); Rf = 0.8 (benzene/chloroform/dieth-
sould be mentioned that the well-established regioselective
methylation at C-1 was used in the final step to generate
carbazomycin G.[5]
Conclusions
ylamine, 14:5:1). UV (MeOH): λ = 236, 300, 358 nm. IR (drift): ν
˜
= 3495 (br), 3292, 2965, 1678, 1620, 1536, 1498, 1442 cm–1. 1H
NMR (500 MHz, CDCl3): δ = 1.21 (d, J = 7.0 Hz, 3 H, CH3),
1.51–2.78 (m, 7 H, 2ϫ 3-H, 2ϫ 4-H, 2ϫ 5-H, 2-H), 6.98 (d, J =
7.5 Hz, 2 H, Ar-H), 7.21–7.30 (m, 3 H, Ar-H), 13.71 (s, 1 H, NH;
exch.) ppm. 13C NMR and DEPT (125 MHz, CDCl3): δ = 14.83
(CH3), 16.32 (CH2), 22.06 (CH2), 31.69 (CH2), 43.71 (CH), 114.36
(CH), 122.84 (CH), 125.91 (CH), 128.99 (CH), 129.40 (CH), 132.29
(C), 143.31 (C), 200.13 (C=O) ppm. HRMS (Q-TOF): m/z calcd.
for C13H16N2ONa [M + Na]+ 239.1154; found 239.1156.
A five-step total synthesis of carbazomycin G has been
established, whereby the initial carbazoloquinone was syn-
thesised through CAN-SiO2-mediated oxidation of easily
available 14 followed by Thiele acetylation on 13 under
HBF4 catalysed conditions and then subsequent oxidative
hydrolysis using CAN-SiO2 in the solid phase to give 10 as
the synthetic precursor. Standard functional group in-
terconversion of the latter generated carbazomycin G. The
present study thus expands the application of two renowned
reagents, CAN-SiO2 and HBF4.
2-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (14): A solution of
18 (10.8 g, 50.0 mmol) in glacial acetic acid (80 mL) containing
conc. hydrochloric acid (20 mL) was heated to reflux for 4 min.
The reaction mixture was poured into ice-water (300 mL) and the
solid thus obtained was collected by filtration, washed with water,
and dried. The residue was subjected to flash chromatography (hex-
ane/CH2Cl2, 7:3) on silica gel to give a white solid. Recrystalli-
zation of the solid from dichloromethane/hexane provided 14
(8.4 g, 84%) as white crystals; m.p. 172–173 °C (ref.[22] 173 °C); Rf
Experimental Section
General: All reactions were carried out with anhydrous solvents.
Melting points were determined in open capillaries and are uncor-
rected. Reagent grade chemicals were purchased from commercial
sources and used without further purification. All reaction mix-
tures and column eluents were monitored by TLC using commer-
cial aluminium TLC plates (Merck Kieselgel 60 F254). The plates
were observed under UV light at 254 and 365 nm. IR spectra were
recorded in KBr discs with a Shimadzu FTIR-8300 spectropho-
tometer, and 1H and 13C NMR spectra were recorded with a
Bruker AV 500 instrument. High-resolution mass spectra (HRMS)
were performed with a Q-TOF Micro YA263 instrument.
= 0.7 (benzene/chloroform/diethylamine, 14:5:1). UV (MeOH): λ =
1
238, 312 nm. IR (drift): ν = 3284, 2932, 1688, 1516, 1492 cm–1. H
˜
NMR (500 MHz, CDCl3): δ = 1.38 (d, J = 8.0 Hz, 3 H, CH3), 2.02
(m, 1 H, 3-H), 2.32 (m, 1 H, 3-H), 2.72 (m, 1 H, 2-H), 2.97 (m, 1
H, 4-H), 3.09 (m, 1 H, 4-H), 7.13 (t, 1 H, Ar-H), 7.35 (t, 1 H, Ar-
H), 7.46 (d, J = 8.5 Hz, 1 H, Ar-H), 7.64 (d, J = 8.5 Hz, 1 H, Ar-
H), 9.68 (s, 1 H, NH; exch) ppm. 13C NMR (CDCl3, 125 MHz): δ
= 15.28 (CH3), 20.60 (CH2), 33.23 (CH2), 41.99 (CH), 112.75 (CH),
120.26 (CH), 121.25 (CH), 125.84 (CH), 126.84 (C), 129.05 (C),
130.98 (C), 138.35 (C), 194.57 (C=O) ppm. HRMS (Q-TOF): m/z
calcd. for C13H13NONa [M + Na]+ 222.0890; found 222.0893.
3-Methyl-2-oxocyclohexanecarbaldehyde (16): A solution of 2-
methylcyclohexanone (15; 11.2 g, 0.1 mol) containing ethyl formate
(18.0 mL, 0.15 mol) and metallic sodium (2.3 g, 0.1 mol) in sodium-
dried diethyl ether (200 mL) was placed in a conical flask with a
magnetic stirrer and guard tube. To initiate the reaction, five drops
of ethanol were added to the stirred mixture, while placing it in a
cold water bath. Stirring was continued for 4 h, whereupon the so-
dium salt of 3-methyl-2-oxocyclohexanecarbaldehyde was obtained
as a cake-like mass. Further ethanol (5 mL) was added, and the
mixture was stirred for an additional 30 min to quench any unre-
acted metallic sodium. Water (150 mL) was then added and the
mixture was shaken in a separating funnel. The aqueous layer was
collected and the organic layer was further extracted with water
2-Methyl-1H-carbazole-1,4(9H)-dione (13): A solution of ceric am-
monium nitrate (8.3 g, 15.0 mmol) in anhydrous acetonitrile
(30 mL) was mixed with silica gel (35 g), then the solvent was evap-
orated at room temperature and the reagent thus obtained was
soaked with a solution of 14 (0.495g, 2.5 mmol) in dichloromethane
(20 mL) followed by evaporation of the solvent in air. The mixture
was kept overnight at room temperature, then the reaction mixture
was extracted with dichloromethane (3ϫ 50 mL) and the solvent
was evaporated to dryness. The residue was purified by chromatog-
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Total Synthesis of Carbazomycin G
raphy (hexane/CH2Cl2, 2:3) over silica gel to furnish a red-coloured
solid, which was crystallized from dichloromethane/hexane to yield
13 (305 mg, 58%) as a red solid; m.p. 225–232 °C (dec.) [ref.[23]
237–239 °C (dec)]. Rf = 0.5 (benzene/chloroform/diethylamine,
(C=O) ppm. HRMS (Q-TOF): m/z calcd. for C13H10NO3
[M + H]+ 228.0657; found 228.0660.
3-Methoxy-2-methyl-1H-carbazole-1,4(9H)-dione (9): A solution of
10 (100.0 mg, 0.4 mmol) in dichloromethane (20 mL) was added
slowly to a solution of diazomethane[24] in CH2Cl2 (6.5 mL, 0.26%
diazomethane solution, 16.8 mg, 0.4 mmol) at room temperature.
After 30 min, vigorous evolution of nitrogen was observed and the
reaction mixture was kept overnight at room temperature. Evapora-
tion of the solvent and column chromatography (hexane/CH2Cl2,
1:4) of the residue on silica gel afforded 9 (89 mg, 92.5%) as an
orange-yellow solid; m.p. 242–245 °C (dec.) [ref.[5] 248–256 °C
(dec)]. Rf = 0.5 (benzene/chloroform/diethylamine, 14:5:1). UV
14:5:1). UV (MeOH): λ = 316 (sh), 257, 217 nm. IR (drift): ν =
˜
3220 (br), 2915, 2883, 1618, 1508, 1490, 1366 cm–1. 1H NMR
(500 MHz, [D6]DMSO): δ = 3.32 (s, 3 H, CH3), 6.54 (d, J = 5.5 Hz,
1 H, 3-H, doublet due to long range coupling with allylic proton
of CH3 gr), 7.26 (t, 1 H, Ar-H), 7.35 (t, 1 H, Ar-H), 7.50 (d, J =
8.5 Hz, 1 H, Ar-H), 7.97 (t, 1 H, Ar-H), 12.79 (s, 1 H, NH,
exch) ppm. 13C NMR (CDCl3, 125 MHz): δ = 15.42 (CH3), 114.21
(CH), 116.06 (CH), 122.15 (CH), 123.69 (CH), 124.19 (CH), 126.77
(C), 135.26 (C), 136.16 (C), 138.12 (C), 144.49 (C), 180.64 (C=O),
183.81 (C=O) ppm. HRMS (Q-TOF): m/z calcd. for C13H10NO2
[M + H]+ 212.0708; found 212.0710.
(MeOH): λ = 362 (sh), 287, 258 nm. IR (drift): ν = 3464 (br), 3286,
˜
2960, 2895, 1625, 1612, 1525 cm–1. 1H NMR (500 MHz, [D6]-
DMSO): δ = 2.50 (s, 3 H, CH3), 3.82 (s, 3 H, OCH3), 7.84 (d, J =
8.0 Hz, 1 H, Ar-H), 8.10 (dd, J = 7.5, 8.0 Hz, 2 H, Ar-H), 8.24 (t,
1 H, Ar-H), 9.67 (s, 1 H, NH, exch) ppm. 13C NMR and DEPT
(125 MHz, [D6]DMSO): δ = 13.87 (CH3), 58.15 (CH3), 113.15
(CH), 114.82 (CH), 118.95 (CH), 123.65 (CH), 126.55(C), 138.49
(C), 139.38 (C), 140.56 (C), 143.65 (C), 145.82 (C), 175.92 (C=O),
180.04 (C=O) ppm. HRMS (Q-TOF): m/z calcd. for C14H11NO3Na
[M + Na]+ 264.0632; found 264.0636.
4-Hydroxy-2-methyl-9H-carbazole-1,3-diyl diacetate (19): The vol-
ume of 48% HBF4 solution (1.0 mL) was reduced to 0.2 mL under
vacuum at 70 °C and then cooled to 0 °C. To this HBF4 solution
at 0 °C, cold acetic anhydride (5.0 mL) was added. The temperature
of the reaction mixture immediately raised due to an exothermic
reaction. The reaction flask was placed over an oil-bath keeping
the temperature 65–70 °C and solid compound 14 (100.0 mg,
0.5 mmol) was added portionwise to the reaction mixture with con-
tinuous stirring over 1 h. After complete addition, the reaction was
continued for a further 5 h. The reaction mixture was then cooled
to 0 °C and poured into ice-water (ca. 100 mL) to obtain a green
solid. The precipitate was isolated by filtration, washed with a large
volume of H2O, and dried in vacuo. Column chromatography (hex-
ane/CH2Cl2, 1:9) of the residue on silica gel furnished 19 (80 mg,
51%) as a yellow solid; m.p. 138 °C (dec); Rf = 0.2 (benzene/chloro-
form/diethylamine, 14:5:1). UV (MeOH): λ = 233, 293, 384 nm. IR
Carbazomycin G (1,4-Dihydro-1-hydroxy-3-methoxy-1,2-dimethyl-
9H-carbazol-4-one; 7): A solution of methyllithium (1.09 M in
Et2O, 2 mL, 2.2 mmol) was added dropwise to a solution of 9
(50 mg, 0.2 mmol) in THF (10 mL) at –78 °C. The reaction mixture
was warmed to room temperature for a period of 30 min, then the
reaction was quenched by the addition of 10% aqueous NH4Cl
(10 mL). The aqueous layer was extracted with dichloromethane
(3ϫ 20 mL) and the combined organic layers were dried with so-
dium sulfate. The solvent was evaporated and column chromatog-
raphy (hexane/CH2Cl2, 3:7) of the residue on silica gel provided
compound 7 (40 mg, 78%) as a yellow solid; m.p. 260–262 °C (dec.)
[ref.[5] 266–268 °C (dec)]. Rf = 0.5 (benzene/chloroform/dieth-
(drift): ν = 3410, 2920, 2856, 1742, 1648, 1610, 1474 cm–1. 1H
˜
NMR (500 MHz, [D6]DMSO): δ = 2.36 (s, 3 H, Ar-CH3), 2.43 (s.
6 H, COCH3), 7.02 (s, 1 H, Ar-H), 7.32 (m, 1 H, Ar-H), 8.22 (d, J
= 7.5 Hz, 1 H, Ar-H), 8.33 (d, J = 8.5 Hz, 1 H, Ar-H), 9.83 (s, 1 H,
NH, exch), 11.60 (br. s, 1 H, Ar-OH) ppm. 13C NMR and DEPT
(125 MHz, [D6]DMSO): δ = 16.55 (CH3), 21.40 (CH3), 21.83
(CH3), 114.88 (CH), 116.90 (CH), 120.22 (CH), 121.92 (C), 122.68
(CH), 125.31 (C), 129.94 (C), 130.22 (C), 132.71 (C), 133.33 (C),
135.09 (C), 142.58 (C), 169.46 (C=O), 169.57 (C=O) ppm. HRMS
(Q-TOF): m/z calcd. for C17H16NO5 [M + H]+ 314.1023; found
314.1026.
ylamine, 14:5:1). IR (drift): ν = 3209 (br), 1643, 1620, 1611, 1482,
˜
1453 cm–1. 1H NMR (500 MHz, [D6]DMSO): δ = 1.93 (s, 3 H,
CH3), 2.39 (s, 3 H, CH3), 3.84 (s, 3 H, OCH3), 5.45 (s, 1 H, OH),
7.26–7.44 (m, 2 H, Ar-H), 7.54–7.58 (m, 1 H, Ar-H), 7.66 (d, J =
8.0 Hz, 1 H, Ar-H), 12.17 (s, 1 H, NH, exch) ppm. 13C NMR and
DEPT (125 MHz, [D6]DMSO): δ = 11.26 (CH3), 13.45 (CH3),
59.17 (CH3), 65.33 (C), 112.35 (CH), 114.22 (CH), 120.95 (CH),
122.85 (CH), 127.54 (C), 137.49 (C), 139.78 (C), 141.51 (C), 143.25
(C), 149.66 (C), 177.82 (C=O) ppm. HRMS (Q-TOF): m/z calcd.
for C15H16NO3 [M + H]+ 258.1125; found 258.1128.
3-Hydroxy-2-methyl-1H-carbazole-1,4(9H)-dione (10): Ceric am-
monium nitrate (548 mg, 1.0 mmol) dissolved in anhydrous aceto-
nitrile (10 mL), was added to silica gel (2.0 g) and the solvent was
then evaporated at room temperature. The reagent was impregnated
with a solution of 19 (156 mg, 0.5 mmol) in dichloromethane
(30 mL) followed by evaporation of solvent. The reaction mixture
was kept overnight at room temperature, then extracted with
dichloromethane (3ϫ 50 mL) and the solvent was evaporated. The
residue was purified by chromatography (hexane/CH2Cl2, 1:4) over
silica gel to provide a red-coloured solid, which was purified by
crystallization from dichloromethane/hexane to yield 10 (78 mg,
67%) as an orange-red solid; m.p. 221 °C; Rf = 0.4 (benzene/chloro-
3-Methoxy-2,9-dimethyl-1H-carbazole-1,4(9H)-dione (20): A solu-
tion of 10 (50.0 mg, 0.2 mmol) in dicholoromethane was added
slowly to a solution of diazomethane[24] in dichloromethane
(10 mL, 0.26% diazomethane solution, 25.8 mg, 0.6 mmol) at room
temperature. Vigorous evolution of nitrogen was observed after
20 min and the reaction mixture was kept overnight. Evaporation
of the solvent and column chromatography (hexane/CH2Cl2, 1:4)
of the residue on silica gel afforded 20 (33 mg, 65%) as a red solid;
m.p. 189 °C (dec.); Rf = 0.4 (benzene/chloroform/diethylamine,
form/diethylamine, 14:5:1). UV (MeOH): λ = 374 (sh), 298, 14:5:1). IR (drift): ν = 3360 (br), 2893, 1634, 1625, 1570 cm–1. H
1
˜
252 nm. IR (drift): ν = 3482 (br), 3376, 2945, 2895, 1628, 1614,
NMR (500 MHz, [D6]DMSO): δ = 2.51 (s, 3 H, CH3), 3.36 (s, 3
H, OCH3), 3.38 (s, 3 H, N-CH3), 7.55- 7.59 (m, 2 H, Ar-H), 7.67–
˜
1510 cm–1. 1H NMR (500 MHz, [D6]DMSO): δ = 2.15 (s, 3 H,
CH3), 7.54–7.63 (m, 1 H, Ar-H), 7.77 (dd, J = 7.5, 8.0 Hz, 1 H, 7.71 (m, 2 H, Ar-H) ppm. 13C NMR and DEPT (125 MHz, [D6]-
Ar-H), 8.02–8.07 (m, 1 H, Ar-H), 8.24 (s, 1 H, Ar-H), 13.58 (s, 1
H, NH, exch), 13.71 (s, 1 H, OH) ppm. 13C NMR and DEPT
(125 MHz, [D6]DMSO): δ = 13.97 (CH3), 112.87 (CH), 114.79
DMSO): δ = 13.61 (CH3), 33.23 (CH3), 59.51 (CH3), 112.45 (CH),
114.82 (CH), 119.95 (CH), 123.65 (CH), 125.51 (C), 138.19 (C),
139.58 (C), 141.56 (C), 143.15 (C), 145.52 (C), 177.62 (C=O),
(CH), 118.93 (CH), 122.60 (CH), 126.55(C), 138.46 (C), 139.38 (C), 178.85 (C=O) ppm. HRMS (Q-TOF): m/z calcd. for C15H14NO3
140.56 (C), 142.56 (C), 144.85 (C), 172.92 (C=O), 177.24 [M + H]+ 256.0969; found 256.0971.
Eur. J. Org. Chem. 2013, 5731–5736
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5735

S. Chakraborty, C. Saha
FULL PAPER
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Received: April 1, 2013
Published Online: July 18, 2013
5736
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Eur. J. Org. Chem. 2013, 5731–5736