A novel CAN-SiO2-mediated one-pot oxidation of 1-keto-1,2,3,4-tetrahydrocarbazoles to carbazoloquinones: Efficient syntheses of murrayaquinone A and koeniginequinone A

Article abstract of DOI:10.1002/jhet.561

One-pot oxidations of substituted 1-keto-1,2,3,4-tetrahydrocarbazoles (1) to carbazole-1,4-quinones (2) are efficiently carried out by CAN-SiO ₂-mediated reaction. This generalized protocol was successfully extended to the synthesis of two naturally occurring carbazoloquinones: murrayaquinone A (2b) and koeniginequinone A (2g). A plausible mechanism for this novel reaction involves formation of a 9-hydroxy-2,3,4,9-tetrahydro-1H- carbazole-1-one followed by rearrangement to 1-hydroxycarbazole derivatives, which are further oxidized by cerium (IV) to carbazoloquinones.

Full text of DOI:10.1002/jhet.561

March 2011
A Novel CAN-SiO2-Mediated One-Pot Oxidation of
1-Keto-1,2,3,4-tetrahydrocarbazoles to Carbazoloquinones:
Efficient Syntheses of Murrayaquinone A and Koeniginequinone A
331
Suchandra Chakraborty,a Gautam Chattopadhyay,b and Chandan Sahaa*
aDepartment of Clinical and Experimental Pharmacology, School of Tropical Medicine,
Kolkata 700073, India
bPostgraduate Department of Chemistry, Presidency College, Kolkata 700073, India
*E-mail: katichandan@yahoo.co.in
Received January 9, 2010
DOI 10.1002/jhet.561
Published online 16 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
One-pot oxidations of substituted 1-keto-1,2,3,4-tetrahydrocarbazoles (1) to carbazole-1,4-quinones
(2) are efficiently carried out by CAN-SiO2-mediated reaction. This generalized protocol was success-
fully extended to the synthesis of two naturally occurring carbazoloquinones: murrayaquinone A (2b)
and koeniginequinone A (2g). A plausible mechanism for this novel reaction involves formation of a 9-
hydroxy-2,3,4,9-tetrahydro-1H-carbazole-1-one followed by rearrangement to 1-hydroxycarbazole deriv-
atives, which are further oxidized by cerium (IV) to carbazoloquinones.
J. Heterocyclic Chem., 48, 331 (2011).
INTRODUCTION
lary muscle [11]. Further carbazole-1,4-quinones [12]
have been used as intermediates in the synthesis of a
novel class of antibiotics, carbazomycines G and H [13].
In addition to the aforementioned oxidations [1] using
DDQ, there are several reported syntheses of carbazole-
1,4-quinones from 1- or 4-oxygenated carbazoles
[10,14–16] via oxidation with Fremy’s salt. A Japanese
team [17] has developed a facile palladium (II) assisted
intramolecular ring closure of arylamino-1,4-benzoqui-
nones to carbazole-1,4-quinones. Knolker and coworkers
[18,19] have taken advantage of this oxidative cycliza-
tion to obtain koeniginequinones A and B and carbazo-
mycines G and H. Chowdhury et al. [20] have reported
a photochemical oxidation of 3-methyl carbazole to
obtain murrayaquinone A. Recently, Mal et al. [21]
have developed a new strategy using [4 þ 2] cycloaddi-
tion to obtain carbazole quinones from furoindolone and
Michael acceptors.
As part of a larger project in our laboratory, we faced
the problem of synthesizing, in quantity, the carbazole-
1,4-quinone (2a). To date, there is only one report [1]
for direct oxidation of 1-keto-1,2,3,4-tetrahydrocarbzoles
to carbazole-1,4-quinones and each cited example uses
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In
our hands, however, this method proved unsuccessful in
the transformation of 1a into 2a (Scheme 1).
This failure motivated us to study the similar oxidation
of 1-keto-1,2,3,4-tetrahydrocarbzoles by using the time-
honored single-electron oxidant, CAN [2–4]. A survey of
the literature [5] revealed that CAN, a single-electron oxi-
dant is a reagent of choice for the synthesis quinones.
It is worth mentioning that substituted 1-keto-1,2,3,4-
tetrahydrocarbazoles have been extensively used as an
intermediate in the synthesis of naturally occurring car-
bazole alkaloids [6]. Cabazole-1,4-quinones are present
in a large group of alkaloids that includes murrayaqui-
nones A and B [7,8], pyrrayaquinones A and B [9], and
koeniginequinones A and B [10]. Murrayaquinone A is
known to have cardiotonic activity on guinea-pig papil-
Considering the importance of carbazole-1,4-quinones
and the easy availability of 1-keto-1,2,3,4-tetrahydroca-
bazoles, we have studied the oxidation of 1-keto-1,2,3,4-
tetrahydrocarbazole (1a) with CAN and CAN/DDQ
C
V
2010 HeteroCorporation

332
S. Chakraborty, G. Chattopadhyay, and C. Saha
Vol 48
Scheme 1. Attempted oxidation of 1a to 2a.
Scheme 2. CAN-SiO2-mediated oxidation to obtain carbazole-1,4-
quinones.
under different conditions. However, because it could
not be accomplished satisfactorily in solution phase, we
had to carry out this reaction on a solid support.
The apparently favorable effect of 3-substitution on
yields in the oxidation reaction of 1 provoked to also
examine the effect of 2-substitution. However, no per-
ceptible change was observed when compared with that
of 3-methyl isomer. Again, presence of an electron-
donating methoxy group in the benzene moiety of 1
lowers the yield of 2, probably because of over oxida-
tion [22]. However, this observation prompted us to
investigate the oxidations of 1-keto-1,2,3,4-tetrahydro-
carzoles (1) with electron-withdrawing group in the phe-
nyl ring. On the basis of this insight, we successfully
synthesized several carbazole-1,4-quinones with elec-
tron-withdrawing group (Table 1). It is worth mention-
ing that, with carbazole-1,4-quinones containing elec-
tron-withdrawing group on the phenyl ring, optimum
yields are formed by heating the reaction for at least 4 h
in an oil bath maintained at ca. 150ꢀC or by microwave
irradiation for 20 s at the power level 80% of 720 W.
It was noted by TLC that a compound with Rf 0.65
(solvent system, benzene–chloroform–diethyl amine
14:5:1) formed alongside quinone 2t (Rf 0.26). The less
polar by-product was isolated by column chromatogra-
phy and identified as 9-hydroxy-6-methoxy-3,7-di-
methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (3) for
which there is a good literature precedent [26] and the
reaction is assumed to proceed as in Scheme 3.
RESULTS AND DISCUSSION
The strong oxidizing power of cerium (IV) salts often
leads to undesired over oxidized products [22]. The con-
cept of moderating the effect of reagents by immobiliz-
ing them on an inorganic solid support has achieved
considerable popularity in organic syntheses [23,24].
Taking advantage of the moderated activity of CAN
when it is immobilized on silica gel, we oxidized 1a in
solid phase under solvent-free conditions and obtained
2a in moderate yield.
Using this finding as a starting point, a new and environ-
mentally safe method for the oxidation of substituted 1-
keto-1,2,3,4-tetrahydrocarbazoles (1) to carbazole-1,4-qui-
nones (2) in single step using CAN-SiO2 has been devel-
oped. The analysis of our observations and characteriza-
tion of the products is the subject of this communication.
Finally, we extend the scope of the reaction to the synthe-
sis of the naturally occurring carbazoloquinones: murraya-
quinone A (2b) and koeniginequinone A (2g) (Fig. 1).
The required substituted 1-keto-1,2,3,4-tetrahydrocar-
bazoles (1) were prepared through Fischer indole cycli-
zation [25] of substituted cyclohexane-1,2-dione-1-phe-
nylhydrazones obtained by Japp-Klingemann procedure
from diazonium salts and 1,3-dicarbonyl compounds.
CAN was dissolved in acetonitrile and then mixed with
requisite amount of silica gel (see Experimental Sec-
tion). Solvent was then evaporated and replaced by a so-
lution of the substituted 1-keto-1,2,3,4-tetrahydrocarba-
zole (1). After re-evaporation, the mixture was kept at
room temperature overnight [monitored by thin layer
chromatography (TLC)], and the product was isolated
and purified (Scheme 2). The results are summarized in
Table 1.
The key steps of the reaction sequence shown above
(Scheme 3) are the oxidation of 1t to 3 followed by 1,4-
elimination of a water molecule and subsequent 1,5-shift of
the hydrogen atom to afford a 1-hydroxycarbazole, which
is oxidized further by CAN to the final product, a 1,4-carba-
zoloquinone 2t. Further identification of 3 was established
through O-acetylation and O-methylation to obtain 6-
methoxy-3,7-dimethyl-1-oxo-3,4-dihydro-1H-carbazol—
9(2H)-yl acetate (13) and 6,9-dimethoxy-3,7-dimethyl-1-
oxo-3,4-dihydro-1H-carbazol-1-one (14), respectively.
We then turned our attention to the conversion of 3 to a
1-hydroxycarbazole under several solid acid catalyzed
conditions using SiO2, acidic Al2O3, SiO2-NH4Cl, mont-
morillonite-K10, and montmorillonite-KSF. However, all
these attempts were unsuccessful and in each case, the
unreacted starting material 3 was almost completely recov-
ered. Finally, we tried the CAN-SiO2-mediated oxidation
on 3 and obtained the desired 1,4-carbazoloquinone 2t.
This observation led to the idea that Ce (IV) may
Figure 1. Representative carbazoloquinones.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011 A Novel CAN-SiO2-Mediated One-Pot Oxidation of 1-Keto-1,2,3,4-tetrahydrocarbazoles
to Carbazoloquinones: Efficient Syntheses of Murrayaquinone A and Koeniginequinone A
333
Table 1
CAN-SiO2 mediated oxidation of 1-keto-1,2,3,4-tetrahydrocarbazoles (1) to carbazole-1,4-quinones (2).
Entry
Substrate
Product
Yield (%)a
References
26
1,8,14,15,17,18
1
2
1a. R1 ¼ R2 ¼ R3 ¼ R4 ¼ R5 ¼ H
2a
2b
55
62
50
60
54
50
56
58
54
52
50
88
92
81
85
85
83
89
88
1b. R1 ¼ R2 ¼ R3 ¼ R5 ¼ H, R4 ¼ CH3
1c. R1 ¼ CH3, R2 ¼ R3 ¼ R4 ¼ R5 ¼ H
1d. R1 ¼ R4 ¼ CH3, R2 ¼ R3 ¼ R5 ¼ H
1e. R1 ¼ R3 ¼ R4 ¼ CH3, R2 ¼ R5 ¼ H
1f. R1 ¼ OCH3, R2 ¼ R3 ¼ R5 ¼ H, R4 ¼ CH3
1g. R1 ¼ R3 ¼ R5 ¼ H, R2 ¼ OCH3, R4 ¼ CH3
1h. R1 ¼ R2 ¼ R3 ¼ R4 ¼ H, R5 ¼ CH3
1i. R1 ¼ R5 ¼ CH3, R2 ¼ R3 ¼ R4 ¼ H
1j. R1 ¼ R3 ¼ R5 ¼ CH3, R3 ¼ R4 ¼ H
1k. R1 ¼ OCH3, R2 ¼ R3 ¼ R4 ¼ H, R5 ¼ CH3
1l. R1 ¼ NO2, R2 ¼ R3 ¼ R4 ¼ R5 ¼ H
1m. R1 ¼ NO2, R2 ¼ R3 ¼ R5 ¼ H, R4 ¼ CH3
1n. R1 ¼ Cl, R2 ¼ R3 ¼ R4 ¼ R5 ¼ H
1o. R1 ¼ Cl, R2 ¼ R3 ¼ R5 ¼ H, R4 ¼ CH3
1p. R1 ¼ Cl, R2 ¼ R3 ¼ R4 ¼ H, R5 ¼ CH3
1q. R1 ¼ Br, R2 ¼ R3 ¼ R4 ¼ R5 ¼ H
1r. R1 ¼ Br, R2 ¼ R3 ¼ R5 ¼ H, R4 ¼ CH3
1s. R1 ¼ Br, R2 ¼ R3 ¼ R4 ¼ H, R5 ¼ CH3
3
4
2cb
2d
–
17
5
2eb
2f
–
17
10,17,18
6
7
2g
2h
8
9
17
17
–
17
–
2i
10
11
12
13
14
15
16
17
18
19
2jb
2k
2lb
2mb
2nb
2o
–
–
17
17
–
2p
2qb
2rb
2sb
–
–
a yields are reported after isolation in pure form.
b spectral data of these unknown compounds are incorporated in the Experimental Section.
participate in the process by forming a complex as
shown in Scheme 4. The ability of Ce (IV) to complex
with aromatic OH groups is previously documented in
literature [27].
troso derivative [29] 5 which on reduction with H2S, NH3
furnished the corresponding amine 6. The amine 6 on
acetylation furnished the acetyl derivative 7 which on
methylation with CH3I and NaOC2H5 gave 8. Compound
8 on hydrolysis with concentrated hydrochloric acid
(HCl) in ethanol afforded the required amine hydrochlor-
ide 9. Diazotization of 9 followed by coupling with 2-
(hydroxymethylene)-5-methylcyclohexanone (10) under
Japp-Klingemann conditions furnished 2-(4-methoxy-3-
To synthesize the starting compound 6-methoxy-3,7-
dimethyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (1t), the
amine hydrochloride 9 was prepared from o-cresol
(Scheme 5) using a method different from that reported
in literature [28]. o-Cresol (4) was converted to the ni-
Scheme 3. Plausible mechanistic details for the oxidation of 1-keto-1,2,3,4-tetrahydrocarbazoles.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

334
S. Chakraborty, G. Chattopadhyay, and C. Saha
Vol 48
Scheme 4. Plausible mechanism for Ce (IV)-mediated pathway for the conversion of 3 to 2t.
methylphenyl)hydrazono-5-methylcyclohexanone (11),
which was cyclized to 1t.
proton was deshielded at around d 7.20–8.20 due to the
carbonyl moiety at 4-C. In addition, the C-5 proton of 2e,
2j, and 2t showed unexpected lower intensity in 1H-NMR
spectra. Moreover, Nuclear Overhauser Effect (NOE)
analysis [8,30] suggested orientation of the 6-O-methyl
group toward C-5 hydrogen.
The presence of a carbazole-1,4-quinone moiety 2a–t
was confirmed by their UV and IR spectra [8] and the
presence of two carbonyl signals at around d 180 in the
1
13C-NMR spectrum. In the H-NMR spectrum, the C-5
Scheme 5. Synthesis of 6-methoxy-3,7-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-1-one.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011 A Novel CAN-SiO2-Mediated One-Pot Oxidation of 1-Keto-1,2,3,4-tetrahydrocarbazoles
to Carbazoloquinones: Efficient Syntheses of Murrayaquinone A and Koeniginequinone A
335
3,6,8-Trimethyl-1H-carbazole-1,4(9H)-dione (2e). m.p. 236ꢀC
(dec.); UV (MeOH): 219 (sh), 258.7, 378.5; IR (KBr): m ¼
In summary, we have developed a very simple, inex-
pensive, nontoxic, and eco-friendly one-pot oxidation of
substituted 1-keto-1,2,3,4-tetrahydrocarbazoles to carba-
zole-1,4-quinones and applied it to the synthesis of the
naturally occurring carbazoloquinones murrayaquinone A
(2b) and koeniginequinone A (2g). The method is fairly
general, although product yields are higher when the phe-
nyl ring of the 1-keto-1,2,3,4-tetrahydrocarbazole starting
material contains an electron-withdrawing substituent.
Isolation of 9-hydroxy-6-methoxy-3,7-dimethyl-2,3,4,9-
tetrahydro-1H-carbazol-1-one (3) during the CAN-SiO2
oxidation of 6-methoxy-3,7-dimethyl-2,3,4,9-tetrahydro-
1H-carbazol-1-one (1t) as an intermediate product, fol-
lowed by its subsequent oxidation to 6-methoxy-3,7-di-
;
3324, 2920, 1669,1647 cmꢁ1 1H-NMR (DMSO-d6, 500
MHz): 1.99 (s, 3H, ArACH3), 2.12 (s, 3H, ArACH3), 2.25 (s,
3H, C3ACH3), 6.52 (s, 1H, C2AH), 7.10 (s, 1H, C7AH), 7.60
(s, 1H, C5AH), 13.16 (s, 1H, NAH, exch.); 13C-NMR
(DMSO-d6, 125 MHz): 15. 42 (þ), 15.74 (þ), 16.42 (þ),
113.28 (þ), 114.42 (ꢁ), 124.12 (þ), 126.99 (ꢁ), 128.84 (ꢁ),
131.42 (ꢁ), 136.29 (ꢁ), 137.28 (þ), 141.74 (ꢁ), 148.21 (ꢁ),
179.47 (ꢁ), 181.14 (ꢁ); HRMS m/z calcd for C15H13NO2Na
[M þ Na]þ 262.0844; found 262.0846.
2,6,8-Trimethyl-1H-carbazole-1,4(9H)-dione (2j). m.p. 239ꢀC
(dec.); UV (MeOH): 223 (sh), 257.7, 370.5; IR (KBr): m ¼
3313, 2929, 1662, 1651 cmꢁ1 1H-NMR (DMSO-d6, 500
;
MHz): 1.98 (s, 3H, ArACH3), 2.28 (s, 3H, ArACH3), 2.55 (s,
3H, C2ACH3), 6.56 (s, 1H, C3AH), 7.18 (s, 1H, C7AH), 7.25
(s, 1H, C5AH), 13.25 (s, 1H, NAH, exch.); 13C-NMR
(DMSO-d6, 125 MHz): 14.79 (þ), 16.42 (þ), 16.87 (þ),
113.53 (þ), 114.30 (ꢁ), 124.16 (þ), 127.01 (ꢁ), 128.99 (ꢁ),
135.05 (ꢁ), 136.51 (þ), 137.24 (ꢁ), 141.82 (ꢁ143.86 (ꢁ),
179.77 (ꢁ), 181.42 (ꢁ); HRMS m/z calcd for C15H14NO2 [M
þ H]þ 240.1024; found 240.1028.
methyl-1H-carbazole-1,4(9H)-dione (2t) suggested
a
plausible mechanism for the reaction. The present study
expands the application of CAN-SiO2-mediated oxidation
in synthetically useful transformations.
EXPERIMENTAL
6-Nitro-1H-carbazole-1,4(9H)-dione (2l). m.p. 233ꢀC (dec.);
UV (MeOH): 246.5, 375; IR (KBr): m ¼ 3244, 2956, 2928,
General methods and materials. Melting points were
determined in open capillaries and are uncorrected. Reagent-
grade chemicals were purchased from a commercial source
and used without further purification. All reaction mixtures
and column eluents were monitored by TLC using commercial
aluminum 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 on Schimadzu FTIR-8300 and
NMR spectra were recorded on Bruker AV 500. Results of
attached proton test—13C-NMR experiments are shown in
parentheses where (þ) denotes CH3 or CH and (ꢁ) denotes
CH2 or C. High-resolution mass spectra (HRMS) were per-
formed on Qtof Micro YA263.
1
1728, 1649 cmꢁ1; H-NMR (CDCl3, 500 MHz): 6.80 (d, J ¼
6.0, 1H, C2AH), 6.82 (d, J ¼ 6.0, 1H, C3AH), 7.52 (dd, J13
¼
15.5, J24 ¼ 26, 1H, C7AH), 8.40 (d, J ¼ 8, 1H, C8AH), 8.65
(d, J ¼ 7.5, 1H, C5AH), 10.64 (s, 1H, NAH, exch.); 13C-
NMR (CDCl3, 125 MHz): 117.06 (ꢁ), 123.47 (þ), 123.84 (þ),
126.88 (ꢁ), 129.97 (ꢁ), 131.14 (þ), 134.26 (ꢁ), 135.32 (þ),
136.33 (ꢁ), 139.02 (þ), 179.11 (ꢁ), 182.85 (ꢁ); HRMS m/z
calcd for C12H6N2O4Na [M
265.0235.
þ
Na]þ 265.0225; found
3-Methyl-6-nitro-1H-carbazole-1,4(9H)-dione (2m). m.p. 230ꢀC
(dec.); UV (MeOH): 246.5, 283, 371; IR (KBr): m ¼ 3298,
2958, 2920, 1726, 1649 cmꢁ1 1H-NMR (CDCl3, 500 MHz):
;
2.20 (s, 3H, C3ACH3), 6.63 (s, 1H, C2AH), 7.50 (dd, J13
¼
Typical experimental procedure for CAN-SiO2-mediated
oxidation of 1b to murrayaquinone A (2b). Ceric ammo-
nium nitrate (15 mmol) was dissolved in dry acetonitrile (30
mL) and then mixed with silica gel (35 gm). Solvent was then
evaporated at room temperature and the reagent was impreg-
nated with the solution of 1b (2.5 mmol) in dichloromethane
(20 mL) followed by evaporation of solvent in air. The mix-
ture was then kept over night at room temperature. After the
reaction, the mixture was extracted with dichloromethane (3 ꢂ
50 mL). The solvent was evaporated to dryness and the residue
was chromatographed over silica gel by eluting successively
with hexane and hexane–dichloromethane (2:3). The eluent
furnished a red-colored solid which was purified by crystalliza-
tion from dichloromethane–hexane to yield murrayaquinone A
(2b), m.p. 242–243ꢀC (lit. m.p. [1] 240–241ꢀC).
7.5, J24 ¼ 7.5, 1H, C7AH), 8.38 (d, J ¼ 7.5, 1H, C8AH), 8.66
(d, J ¼ 7.5, 1H, C5AH), 10.56 (s, 1H, NAH, exch.); 13C-
NMR (CDCl3, 125 MHz): 15.23 (þ), 117.06 (ꢁ), 122.95 (þ),
123.34 (þ), 128.04 (ꢁ), 129.5 (ꢁ), 131.42 (þ), 132.20 (þ),
135.32 (ꢁ), 136.30 (ꢁ), 148.70 (ꢁ), 179.11 (ꢁ), 182.85 (ꢁ);
HRMS m/z calcd for C13H8N2O4Na [M þ Na]þ 279.0382;
found 279.0382.
6-Chloro-1H-carbazole-1,4(9H)-dione (2n). m.p. 248ꢀC (dec.);
UV (MeOH): 225.5, 258.7, 383; IR (KBr): m ¼ 3201, 2991,
1666, 1635 cmꢁ1 1H-NMR (DMSO-d6, 500 MHz): 6.76 (s,
;
1H ꢂ 2, C2AH & C3AH), 7.52 (d, J ¼ 8.5, 1H, C7AH), 7.54
(d, J ¼ 8.5, 1H, C8AH), 7.95 (s, 1H, C5AH), 13.08 (s, 1H,
NAH, exch.); 13C-NMR (DMSO-d6, 125 MHz): 114.69 (ꢁ),
115.53 (þ), 120.42 (þ), 124.06 (ꢁ), 126.56 (þ), 128.43 (ꢁ),
135.48 (þ), 135.77 (ꢁ), 136.40 (ꢁ), 138.67 (þ), 179.66 (ꢁ),
182.80 (ꢁ); HRMS m/z calcd for C12H7NO2Cl [M þ H]þ
232.0165; found 232.0168.
6-Methyl-1H-carbazole-1,4(9H)-dione (2c). m.p. 238ꢀC
(dec.); UV (MeOH): 224 (sh), 255.5, 388; IR (KBr): m ¼
1
3178, 2928, 1662,1636 cmꢁ1; H-NMR (DMSO-d6, 500 MHz)
2.41 (s, 3H, ArACH3), 6.69 (s, 1H ꢂ 2, C2AH & C3AH),
7.20 (s, 1H, C7AH), 7.41 (s, 1H, C8AH), 7.80 (s, 1H, C5AH),
12.76 (s, 1H, NAH, exch.); 13C-NMR (DMSO-d6, 125 MHz):
21.20 (þ), 113.46 (þ), 114.92 (þ), 120.93 (þ), 123.61 (ꢁ),
128.32 (ꢁ), 133.28 (ꢁ), 135.28 (þ), 135.28 (þ), 135.84
(ꢁ),138.72 (ꢁ),179.77 (ꢁ), 183.11 (ꢁ); HRMS m/z calcd for
C13H9NO2Na [M þ Na]þ 234.0531; found 234.0581.
6-Bromo-1H-carbazole-1,4(9H)-dione (2q). m.p. 254ꢀC (dec.);
UV (MeOH): 224, 259, 388; IR (KBr): m ¼ 3200, 2987, 1664,
1
1637 cmꢁ1; H-NMR (DMSO-d6, 500 MHz): 6.78 (s, 1H ꢂ 2,
C2AH & C3AH), 7.53 (s, 1H ꢂ 2, C7AH & C8AH), 8.14 (s,
1H, C5AH), 13.11 (s, 1H, NAH, exch.); 13C-NMR (DMSO-d6,
125 MHz): 114.55 (ꢁ), 115.91 (þ), 116.48 (ꢁ), 123.54 (þ),
124.66 (ꢁ), 129.09 (þ), 135.55 (þ), 136.02 (ꢁ), 136.25 (ꢁ),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

336
S. Chakraborty, G. Chattopadhyay, and C. Saha
Vol 48
138.70 (þ), 179.70 (ꢁ), 182.88 (ꢁ); HRMS m/z calcd for
C12H6NO2BrNa [M þ Na]þ 297.9479; found 297.9482.
3-Methyl-6-bromo-1H-carbazole-1,4(9H)-dione (2r). m.p.
257ꢀC (dec.); UV (MeOH): 225.5, 258.7, 322, 392; IR (KBr):
product was leached with 1% NaOH solution (150 mL), fil-
tered, and washed with ice cooled water (100 mL). Compound
8 was crystallized from MeOH-H2O to furnish colorless nee-
dles (8 gm, 75%), m.p. 105ꢀC (lit. m.p. [32] 103–3.5ꢀC). IR:
3310 (ANH), 1654 (C¼¼O), and 1560, 1510 cmꢁ1 (aromatic).
4-Methoxy-3-methylaniline hydrochloride (9). 4-Methoxy-
3-methylacetanilide (7, 35.8 gm, 0.20 mol) was dissolved in
ethanol (100 mL) by boiling and concentrated HCl (100 mL)
was added dropwise under reflux during 1 h. After 3 h, the so-
lution was cooled when the crystals of amine hydrochloride
(9) separated out, which was collected by filtration to furniþsh
1
m ¼ 3205, 2985, 1667, 1640 cmꢁ1; H-NMR (DMSO-d6, 500
MHz): 2.03 (s, 3H, C3ACH3), 6.57 (s, 1H, C2AH), 8.06 (s,
1H, C7AH), 8.20 (s, 1H ꢂ 2, C5AH & C8AH), 12.94 (s, 1H,
NAH, exch.); 13C-NMR (DMSO-d6, 125 MHz): 15.49 (þ),
114.49 (ꢁ), 116.31 (þ), 124.13 (þ), 124.84 (ꢁ), 129.31 (þ),
131.65 (þ), 135.98 (ꢁ), 136.32 (ꢁ), 139.37 (ꢁ), 147.89 (ꢁ),
179.66 (ꢁ), 182.53 (ꢁ); HRMS m/z calcd for C13H8NO2BrNa
[M þ Na]þ 311.9636; found 311.9638.
colorless crystals (27.8 gm, 80%), IR: 3440–3400 (ANH3
)
2-Methyl-6-bromo-1H-carbazole-1,4(9H)-dione (2s). m.p.
258ꢀC (dec.); UV (MeOH): 224, 258.7, 325, 397; IR (KBr): m
and 1600, 1540, 1510 cmꢁ1 (aromatic).
2-(4-Methoxy-3-methylphenyl)hydrazono-5-methylcyclohex-
anone (12). 2-Hydroxymethylene-5-methylcyclohexanone [10]
(11, 16.20 gm, 0.12 mol) in methanol (150 mL) was added to
an aqueous solution of sodium acetate (26 gm, 100 mL of
water). To this a solution of 4-methoxy-3-methylphenyldiazo-
nium chloride [10] (10, prepared from 20.8 gm, 0.12 mol of 4-
methoxy-3-methylaniline hydrochloride) was added during 1 h
under mechanical agitation when red crystals of 12 were
obtained. Filtration and crystallization from methanol–
dichloromethane yielded reddish brown crþystals (12, 26.50 gm,
85%), m.p. 111–112ꢀC. MS: m/z 260 (M ); IR: 3450 (ANH),
1630 (C¼¼O), and 1600, 1510 cmꢁ1 (aromatic).
¼ 3203, 2983, 1668, 1645 cmꢁ1
;
1H-NMR (DMSO-d6, 500
MHz): 2.02 (s, 3H, C2ACH3), 6.56 (s, 1H, C3AH), 7.43A7.53
(m, 1H ꢂ 2, C7AH & C8-H), 8.18 (s, 1H, C5AH), 12.97 (s,
1H, NAH, exch.); 13C-NMR (DMSO-d6, 125 MHz): 15.19
(þ), 114.65 (ꢁ), 115.74 (þ), 124.03 (þ), 124.35 (ꢁ), 124.50
(ꢁ), 128.81 (þ), 134.66 (þ), 136.35 (ꢁ), 139.44 (ꢁ), 144.20
(ꢁ), 179.85 (ꢁ), 182.83 (ꢁ); HRMS m/z calcd for
C13H9NO2Br [M þ H]þ 289.9816; found 289.9816.
Preparation and oxidation of 6-methoxy-3,7-dimethyl-
2,3,4,9-tetrahydro-1H-carbazol-1-one (1t). 2-Methyl-4-nitro-
sophenol (5). To a solution of o-cresol (4, 10.8 gm, 0.1 mol)
in 95% ethanol (80 mL), concentrated HCl (75 mL) was
added. The mixture was cooled to 0ꢀC and to the stirred solu-
tion sodium nitrite (10.5 gm, 0.15 mol) was added in portions
of about 1 gm each while maintaining the reaction temperature
at 0–5ꢀC. Initially, a brown precipitate appeared which turned
greenish within half an hour. The reaction mixture was then
poured in ice water (400 mL). The light yellow solid (yield
7.5 gm) was collected by filtration and washed with cold water
(100 mL). This crude product was used in the next step with-
out further purification.
6-Methoxy-3,7-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-1-one
(1t). 2-(4-Methoxy-methyl phenyl)hydrazono-5-methylcyclo-
hexanone (12, 5.2 gm, 0.02 mol) was refluxed with glacial
acetic acid (30 mL) containing concentrated HCl (7 mL) for 5
min and the hot reaction mixture was poured in ice water (200
mL). The solid thus obtained was collected by filtration,
washed with water, dried, and then chromatographed over
silica gel (50 gm) and the column was eluted with hexane–
dichloromethane (2:1). The eluent gave a colorless solid which
on crystallization from dichloromethane–hexane furnished col-
orless crystals (1t, 3.2 gm, 66%), m.p. 248ꢀ. IR (KBr): m ¼
4-Amino-2-methylphenol (6). The crude nitroso derivative
(5, 30 gm) was dissolved in a mixture of 28% aqueous ammo-
nia (300 mL) and water (400 mL). The brown solution was
then filtered and H2S was passed until light yellow amino
compound (6) was precipitated out. The reaction mixture was
kept over night in refrigerator for complete crystallization of 6
(22 g, 81%), m.p. 173ꢀC (lit. m.p. [31] 175.4ꢀC). IR: 3390
(AOH), 3300 (ANH2), and 1600, 1555, 1500 cmꢁ1 (aromatic).
4-Acetamido-2-methylphenol (7). 4-Amino-2-methylphenol
(6, 24.6 gm, 0.20 mol) was suspended in water (60 mL) and
acetic anhydride (24 mL, 0.25 mol) was added with vigorous
stirring. The mixture was warmed at about 60–65ꢀC for 30
min. On cooling, a solid was separated out which was col-
lected by filtration and washed with cold water. The acetyl de-
rivative 7 was crystallized from water with charcoal treatment
to yield colorless needle-shaped crystals (27.75 gm, 84%),
m.p. 178ꢀC (lit. m.p. [28] 179ꢀC). IR: 3315 (AOH), 3285
(ANH), 1652 (C¼¼O), and 1605, 1542, 1500 cmꢁ1 (aromatic).
4-Methoxy-3-methylacetanilide (8). Clean sodium (1.5 gm,
0.065 mol) was placed in absolute alcohol (40 mL). After the
dissolution of sodium, the mixture was cooled and 4-acet-
amido-2-methylphenol (10 gm, 0.06 mol) was added. Iodome-
thane (15.6 gm, 0.11 mol) was added slowly to the mixture
under reflux using pressure equalizer. After 1-h reaction, mix-
ture was poured in ice water (100 mL), cooled in ice bath, and
crude methylated product was thus separated out. The crude
1
3255, 2997, 2829, 1648 cm–1; H-NMR (CDCl3 þ DMSO-d6,
500 MHz): 1.15 (d, J ¼ 3.50 Hz, 3H, C3ACH3), 2.25 (s, 3H,
ArACH3), 2.29–2.54 (m, 3H, C2A2H & C3A1H), 3.06 (d, J ¼
15.30 Hz, 2H, C4A2H), 3.82 (s, 3H, ArAOCH3), 6.97 (s, 1H,
C8AH), 7.15 (s, 1H, C5AH), 11.22 (br, 1H, NAH, exch); 13C-
NMR (CDCl3 þ DMSO-d6, 125 MHz): 17.22 (þ), 21.06 (þ),
29.29 (ꢁ), 32.47 (þ), 46.16 (ꢁ), 55.11 (þ), 99.29 (þ), 113.59
(þ), 122.39 (ꢁ), 126.82 (ꢁ), 127.37 (ꢁ), 130.47 (ꢁ), 133.36
(ꢁ), 152.39 (ꢁ), 189.15 (ꢁ); HRMS m/z calcd for
C15H17NO2Na [M þ Na]þ 266.1156; found 266.1176.
9-Hydroxy-6-methoxy-3,7-dimethyl-2,3,4,9-tetrahydro-1H-
carbazol-1-one (3) and 6-Methoxy-3,7-dimethyl-1H-carba-
zole-1,4(9H)-dione (2t). The immobilized CAN-SiO2 reagent
was impregnated with the solution of 1u (603 mg, 2.5 mmol)
in dichloromethane–acetonitrile mixture (1:1, 80 mL) followed
by evaporation of solvent in air. The mixture was then kept
over night at room temperature. After the reaction, the mixture
was extracted with dichloromethane (4 ꢂ 50 mL). The solvent
was evaporated to dryness and the residue so obtained was
chromatographed over silica gel (15 gm) by eluting succes-
sively with hexane and mixtures of hexane and dichlorome-
thane in the ratio 1:1 followed by 2:3. The eluent from hex-
ane–dichloromethane (1:1) furnished a reddish brown-colored
solid which was purified by crystallization from dichlorome-
thane–hexane to yield 3 (100 mg, 16%), m.p. 206ꢀC; UV
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011 A Novel CAN-SiO2-Mediated One-Pot Oxidation of 1-Keto-1,2,3,4-tetrahydrocarbazoles
to Carbazoloquinones: Efficient Syntheses of Murrayaquinone A and Koeniginequinone A
337
(MeOH): 233 (sh), 316.5; IR (KBr): m ¼ 3244, 2959, 2928,
thane (3:2) furnished a light yellow-colored solid which was
crystallized to obtain 14 (90 mg, 85%), m.p. 143ꢀC; UV
(MeOH): 240 (sh), 325; IR (KBr): m ¼ 2968, 2933, 1681
1
2871, 1649 cmꢁ1; H-NMR (CDCl3, 300 MHz): 1.18 (d, J ¼
4.11 Hz, 3H, C3ACH3), 1.81 (s, 1H, NAOH), 2.37–2.54 (m,
1H, & C3A1H), 2.46 (s, 3H, ArACH3), 2.66 (d, J ¼ 10.23,
2H, C2A2H), 2.91 (d, J ¼ 14.43 Hz, 2H, C4A2H), 3.90 (s,
3H, ArAOCH3), 7.26 (s, 1H, C8AH), 7.45 (s, 1H, C5AH);
13C-NMR (CDCl3, 75 MHz): 17.03 (þ), 21.28 (þ), 29.66 (ꢁ),
32.61 (þ), 46.12 (ꢁ), 62.75 (þ), 116.37 (þ), 117.33 (þ),
125.95 (ꢁ), 132.79 (ꢁ), 132.88 (ꢁ), 135.50 (ꢁ), 136.47 (ꢁ),
145.59 (ꢁ), 191.97 (ꢁ); HRMS m/z calcd for C15H18NO3 [M
þ H]þ 260.1286; found. 260.1258. Further the eluent from
hexane–dichloromethane (2:3) provide a red-colored solid
which on crystallization from dichloromethane–hexane yielded
2t (350 mg, 55%), m.p. 222ꢀC (dec.); UV (MeOH): 222,
258.5, 378.5; IR (KBr): m ¼ 3323, 2924, 1724, 1651, 1616
1
cmꢁ1; H-NMR (CDCl3, 600 MHz) 1.18 (d, J ¼ 5.4 Hz, 3H,
C3ACH3), 2.41 (s, 3H, ArACH3), 2.50 (q, 1H, C3A1H), 2.71
(d, J ¼ 14.15, 2H, C2A2H), 2.75 (d, J ¼ 13.74 Hz, 2H,
C4A2H), 3.82 (s, 3H, ArAOCH3), 3.97 (s, 3H, NAOCH3),
7.19 (s,1H, C8AH), 7.23 (s, 1H, C5AH); 13C-NMR (CDCl3,
125 MHz): 17.26 (þ), 20.22 (þ), 29.33 (þ) , 31.79 (ꢁ), 46.89
(ꢁ) 62.80 (þ), 65.73 (þ), 94.85 (þ), 114.47 (þ), 114.90 (ꢁ),
122.73 (ꢁ), 130.49 (ꢁ), 131.64 (ꢁ), 137.10 (ꢁ), 145.02 (ꢁ),
198.19 (ꢁ).
Oxidation of 3. The CAN-SiO2 reagent was soaked with the
solution of 3 (130 mg, 0.5 mmol) in dichloromethane (7 mL)
and solvent was removed. The mixture was then kept over
night at room temperature. The reaction mixture was then
extracted with dichloromethane (2 ꢂ 50 mL). The solvent was
removed and the residue so obtained was chromatographed
over silica gel (10 gm) by eluting successively with hexane
and hexane–dichloromethane (2:3). The eluent provided a red-
colored solid which was crystallized from dichloromethane–
hexane to yield 2t (100 mg, 78%).
1
cmꢁ1; H-NMR (DMSO-d6, 500 MHz) 2.03 (s, 3H, ArACH3),
2.43 (s, 3H, C3ACH3), 3.81 (s, 3H, ArAOCH3), 6.67(s, 1H,
C2AH), 7.47 (s, 1H, C8AH), 7.58 (s, 1H, C5AH); 13C-NMR
(DMSO-d6, 125 MHz): 15.72 (þ), 16.31 (þ), 62.58 (þ),
113.22 (ꢁ), 113.39 (ꢁ), 117.54 (þ), 131.55 (þ), 131.65 (ꢁ),
134.68 (ꢁ), 137.55 (ꢁ), 138.16 (þ), 146.08 (ꢁ), 148.24 (ꢁ),
179.48 (ꢁ), 181.28 (ꢁ); HMQC spectrum: dH (ppm):7.58
(C5AH) dC (ppm): 118.41 (C5); HRMS m/z calcd for
C15H13NO3Na [M þ Na]þ 278.0793; found 278.0794.
Acknowledgments. The authors are thankful to Prof. Krishnang-
shu Roy, Director, School of Tropical Medicine, Kolkata and
Prof. Pratip Bhattacharya, Director, Enhanced Magnetic Reso-
nance Laboratory, HMRI, Pasadena, CA 91105, USA for their in-
terest in the work. They are also thankful to Council of Scientific
and Industrial Research (CSIR), New Delhi, India for providing a
Junior Research Fellowship [Grant No. 09/951(0001)/2008-
EMR-I] to one (S. Chakraborty) of the authors.
6-Methoxy-3,7-dimethyl-1-oxo-3,4-dihydro-1H-carbazol—
9(2H)-yl acetate (13). A mixture 3 (130 mg, 0.5 mmol), dry
acetic anhydride (4.0 mL, 4.4 gm, 43 mmol), 4-(dimethylami-
no)pyridine (50.0 mg), and dry pyridine (two drops) was
heated on water bath for 8 h. The reaction mixture was cooled
and poured in ice water (50 mL), the whole mixture was
extracted with ether (4 ꢂ 25 mL), the combined ether extract
was washed with 5% NaHCO3 solution until the evolution of
carbon dioxide ceased, and then the organic phase was washed
with brine solution (50 mL). Ether layer was dried over anhy-
drous Na2SO4 and evaporated. The residue was chromato-
graphed over silica gel (10 gm) and elution with hexane–
dichloromethane (3:2) furnished a light yellow-colored solid
which on crystallization yielded 13 (120 mg, 80%), m.p.
123ꢀC; UV (MeOH): 237 (sh), 320; IR (KBr): m ¼ 2956,
REFERENCES AND NOTES
[1] Ramesh, K.; Kapil, R. S. J Nat Prod 1987, 50, 932.
[2] Molander, G. A. Chem Rev 1992, 92, 29.
[3] Nair, V.; Mathew, J.; Prabhakaran, J. Chem Soc Rev 1997,
26, 127.
[4] Hwu, J. R.; King, K.-Y. Curr Sci 2001, 81, 1043.
[5] Thomson, R. H. Naturally Occurring Quinones III: Recent
Advances; Chapman and Hall Ltd.: London, 1987.
[6] Knolker, H.-J.; Reddy, K. R. Chem Rev 2002, 102, 4303.
[7] Wu, T.-S.; Ohta, T.; Furukawa, H. Heterocycles 1983, 20,
1267.
1
2929, 1716, 1678 cmꢁ1; H-NMR (CDCl3, 300 MHz) 1.12 (d,
J ¼ 5.1 Hz, 3H, C3ACH3), 2.18–2.47 (m, 1H, C3A1H), 2.44
(s, 3H, ArACH3), 2.53 (s, 3H, OCOCH3), 2.65 (d, J ¼ 14.15,
2H, C2A2H), 2.77 (d, J ¼ 13.74 Hz, 2H, C4A2H), 3.82 (s,
3H, ArAOCH3), 7.32 (s, 1H, C8AH), 8.11 (s, 1H, C5AH);
13C-NMR (CDCl3, 75 MHz): 17.25 (þ), 20.86 (þ), 27.55 (þ),
29.82 (ꢁ), 31.17 (þ), 46.83 (ꢁ) 62.75 (þ), 116.79 (ꢁ), 119.78
(þ), 128.65 (þ), 133.47 (ꢁ), 133.57 (ꢁ), 135.55 (ꢁ), 135.65
(ꢁ), 146.73 (ꢁ), 171.95 (ꢁ), 189.38 (ꢁ).
[8] Furukawa, H.; Wu, T. S.; Ohta, T.; Kuoh, C.-S. Chem
Pharm Bull 1985, 33, 4132.
[9] Furukawa, H.; Yogo, M.; Ito, C.; Wu, T.-S.; Kuoh, C.-S.
Chem Pharm Bull 1985, 33, 1320.
[10] Saha, C.; Chowdhury, B. K. Phytochemistry 1998, 48, 363.
[11] Takeya, K.; Itoigawa, M.; Furukawa, H. Eur J Pharmacol
1989, 169, 137.
6,9-Dimethoxy-3,7-dimethyl-1-oxo-3,4-dihydro-1H-carbazol-
1-one (14). The compound 3 (100 mg, 0.38 mmol) was dis-
solved in dry benzene–N,N-dimethylformamide (DMF) mixture
(2:1, 15 mL). After cooling the solution to 0ꢀC, 60% sodium
hydride in paraffin (60 mg, 1.5 mmol) was added to it. The
reaction mixture was cooled in ice bath and iodomethane (600
mg, 4.2 mmol) was added with stirring. The stirring was con-
tinued for 7 h. The reaction mixture was poured in ice water
(50 mL) and the whole mixture was extracted with dichloro-
methane (4 ꢂ 25 mL). The combined dichloromethane extract
was washed with brine solution (25 mL), dried over anhydrous
Na2SO4, and evaporated, and the residue was chromatographed
over silica gel (8.5 gm) and elution with hexane–dichlorome-
[12] Knolker, H.-J.; Frohner, W. J Chem Soc Perkin Trans 1
1998, 2, 173.
[13] Kaneda, M.; Naid, T.; Kitahara, T.; Nakamura, S.; Hirata,
T.; Suga, T. J Antibiot 1988, 41, 602.
[14] Miki, Y.; Hachiken, H. Synlett 1993, 5, 333.
[15] Martin, T.; Moody, C. J. J Chem Soc Perkin Trans 1 1988,
2, 235.
[16] Martin, T.; Moody, C. J. J Chem Soc Perkin Trans 1 1988,
2, 241.
[17] Yogo, M.; Ito, C.; Furukawa, H. Chem Pharm Bull 1991,
39, 328.
[18] Knolker, H.-J.; Reddy, K. R. Heterocycles 2003, 60, 1049.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

338
S. Chakraborty, G. Chattopadhyay, and C. Saha
Vol 48
[19] Knolker, H.-J.; Frohner, W. Eur J Org Chem 2003, 4,
740.
[20] Chowdhury, B. K.; Jha, S.; Kar, B. R.; Saha, C. Indian J
[26] Benzies, D. W. M.; Jones, R. A. J Chem Soc Chem Com-
mun 1986, 13, 1019.
[27] Sathunuru, R.; Narasimha Rao, U.; Biehl, Ed. ARKIVOC
2003, xv, 124.
Chem B 1999, 38, 1106.
[21] Mal, D.; Senapati, B. K.; Pahari, P. Tetrahedron 2007, 63,
3768.
[28] Harvision, P. J.; Forte, A. J.; Nelson, S. D. J Med Chem
1986, 29, 1737.
[22] Chawla, H. M.; Mittal, R. S. Synthesis 1985, 1, 70.
[23] Hwu, J. R.; Jain, M. L.; Tsai, F.-Y.; Tsay, S.-C.; Balaku-
mar, A.; Hakimelahi, G. H. J Org Chem 2000, 65, 5077.
[24] Banarjee, S.; Sarkar, S.; Basak, R.; Chakraborty, M. J In-
dian Chem Soc 2004, 81, 169.
[29] Albert, H. E. J Am Chem Soc 1954, 76, 4985.
[30] Chakravarty, A. K.; Sarkar, T.; Masuda, K.; Shiojima, K.
Phytochemistry 1999, 50, 1263.
[31] Dey, A.; Kirchmer, M. T.; Vangala, V. R.; Desiraju, G. R.;
Mondal, R.; Howard, J. A. K. J Am Chem Soc 2005, 127, 10545.
[32] Heidelderger, M.; Jacobs, W. A. J Am Chem Soc 1919, 41,
1450.
[25] Saha, C.; Chakraborty, A.; Chowdhury, B. K. Indian J
Chem B 1996, 35, 677.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet