Synthesis and Diels-Alder reactivity of ortho-carbazolequinones

Article abstract of DOI:10.1248/cpb.52.1114

Oxidation of 2- and 3-hydroxycarbazoles with Fremy's salt gave the corresponding ortho-carbazolequinones. These molecules react as carbodienophiles in Diels-Alder reaction with 1-acetoxy-1,3-butadiene and 1,3-cyclopentadiene to provide the novel benzocarbazolequinone structures 15, 16, 18 and 19.

Full text of DOI:10.1248/cpb.52.1114

1114
Notes
Chem. Pharm. Bull. 52(9) 1114—1116 (2004)
Vol. 52, No. 9
Synthesis and Diels–Alder Reactivity of ortho-Carbazolequinones
Muriel COMPAIN-BATISSOU, Djamila LATRECHE, Jacques GENTILI, Nadia WALCHSHOFER, and
Zouhair BOUAZIZ*
Laboratoire de Chimie Organique, Institut des Sciences Pharmaceutiques et Biologiques, Université Claude Bernard
Lyon1; 8 avenue Rockefeller, 69373 Lyon cedex 08, France. Received February 2, 2004; accepted June 9, 2004
Oxidation of 2- and 3-hydroxycarbazoles with Frémy’s salt gave the corresponding ortho-carbazolequinones.
These molecules react as carbodienophiles in Diels–Alder reaction with 1-acetoxy-1,3-butadiene and 1,3-cy-
clopentadiene to provide the novel benzocarbazolequinone structures 15, 16, 18 and 19.
Key words ortho-carbazolequinone; Diels–Alder reaction; benzocarbazolequinone
chemoselectively the N-methylated compound 2.12) Then, ox-
The carbazole-3,4-quinones represent an important family
idation of 2 with Frémy’s salt afforded carbazole-1,2-quinone
4.
of carbazole alkaloids. Carquinostatins A and B, lavan-
duquinocin and carbazoquinocins A—F represent the first
carbazole alkaloids containing an ortho-quinone system1) and
possess various biologic activities (Chart 1).
The carquinostatins A and B were isolated from Strepto-
myces exfoliatus 2419-SVT2 and were shown to be potent
neuronal protecting substances.2,3) Lavanduquinocin was iso-
lated from Streptomyces viridochromogenes 2942-SVS3 and
exhibit a strong neuronal cell protecting activity.4) The car-
bazoquinocins A—F were isolated from Streptomyces vio-
laceus 2448-SVT2 and they showed strong inhibitory activity
against lipid peroxydation.5)
As part of our continuing search for biologically active
compounds with a quinone moiety, we were particularly in-
terested in the synthesis and in the Diels–Alder chemistry of
carbazolequinones.6) In a previous work we reported the syn-
thesis,7,8) the induction of caspase-dependent cell death9) and
the Toxoplasma gondii purine nucleoside phosphorylase in-
hibitory activity10) of some carbazole-1,4-quinones.
On the other hand, carbazole-3,4-quinone 7 was obtained
in two steps from the commercially available 3-aminocar-
bazole 5. The formation of the corresponding diazonium salt
at 0 °C followed by heating the latter in highly acidic aqueous
solution gave the 3-hydroxycarbazole 6, which was oxidized
as above to yield quinone 7 (Chart 2).
Our attempts to obtain 7 through a direct oxidation of 5
with Frémy’s salt provided the dimeric carbazole compounds
12 and 13 only. The reaction may proceed first by formation
of a mixture of amino phenol 8 and ortho-quinone imine 9.
Then, a nucleophilic addition of primary amine 5 or 8 to
quinone imine 9 led to intermediates 10 and 11 which were
subsequently oxidized to the dimeric carbazoles 12 and 13
(Chart 3). Aromatic amines which have a position para to the
amino group substituted by an alkyl or alkoxy group have
been reported to undergo a similar reaction.13,14)
The purpose of this work is to obtain carbazole-1,2 and
-3,4-dione derivatives and to report their behaviour as
dienophiles in [4ꢀ2] cycloaddition reactions.
Results and Discussion
Carbazole-1,2-quinone 311) was obtained by oxidation of
the commercially available hydroxycarbazole 1 with Frémy’s
salt. Treatment of 1 with sodium hydride in the presence of
methyl iodide in the solvent system THF–DMF, gave
Chart 2
Chart 1
Chart 3
* To whom correspondence should be addressed. e-mail: bouaziz@univ-lyon1.fr
© 2004 Pharmaceutical Society of Japan

September 2004
1115
Experimental
Melting points were taken in a capillary tube using a Büchi 510 apparatus.
The IR spectra were obtained on a Perkin–Elmer 1310 spectrophotometer.
The NMR spectra were recorded with a Bruker AM 300 spectrometer (1H-
NMR: 300 MHz, 13C-NMR: 75 MHz). Chemical shifts are reported in ppm
using tetramethylsilane (TMS) as an internal reference. Coupling constant
values are given in Hz. Elemental analyses were performed at the Centre de
Microanalyse du CNRS at Solaize, France.
2-Hydroxy-9-methyl-9H-carbazole (2) A solution of 2-hydroxycar-
bazole 1 (0.457 g, 2.5 mmol) and DMF (0.37 ml, 4.76 mmol) in dry THF
(5 ml) was added dropwise to 60% NaH (0.25 g, 6.25 mmol) under a nitro-
gen atmosphere and stirring at room temperature. After 10 min, CH3I
(0.17 ml, 2.75 mmol) was added and the stirring was continued for 2 h. The
resulting mixture was cooled to 0 °C and quenched with water (2 ml). After
removing the solvent under vacuum, the crude product was washed with
acidic aqueous solution and purified by column chromatography on silica
gel with CH2Cl2/MeOH (98 : 2) as the eluent. Compound 2 was obtained as
a yellow solid in 80% yield (ref. 12, 89%), mp 162 °C (ref. 12, 166—
Chart 4
1
167 °C). IR (KBr) cmꢁ1: 3360. H-NMR (DMSO-d6) d: 9.53 (1H, s, OH),
7.96 (1H, d, Jꢂ7.7 Hz, H-5), 7.89 (1H, d, Jꢂ8.3 Hz, H-4), 7.48 (1H, d,
Jꢂ8.2 Hz, H-8), 7.34 (1H, td, Jꢂ8.2, 1.1 Hz, H-7), 7.13 (1H, td, Jꢂ7.7,
1.0 Hz, H-6), 6.86 (d, 1H, Jꢂ2.0 Hz, H-1), 6.68 (1H, dd, Jꢂ8.3, 2.0 Hz, H-
3), 3.76 (3H, s, CH3-9).
General Method for the Oxidation of Hydroxycarbazoles with
Frémy’s Salt An aqueous solution (20 ml) of Frémy’s salt (0.37 g,
1.37 mmol) and potassium dihydrogen orthophosphate (0.02 g, 0.15 mmol)
was added to a solution of hydroxycarbazole 1, 2 or 6 (0.55 mmol) in ace-
tone (20 ml). The reaction mixture was stirred at room temperature for
30 min, extracted with CH2Cl2, dried over Na2SO4 and concentrated under
vacuum.
Chart 5
1,2-Dihydrocarbazole-1,2(9H)-dione (3) The quinone 3 was obtained
from hydroxycarbazole 1. The crude mixture was purified by column chro-
matography on silica gel using CH2Cl2/MeOH (95 : 5) as the eluent. Com-
pound 3 was obtained as a dark green solid in 64% yield (ref. 11, 83%), mp
181 °C (ref. 11, 178 °C). IR (KBr) cmꢁ1: 3260, 1665, 1640. 1H-NMR
(DMSO-d6) d: 12.61 (1H, s, NH), 7.87 (2H, m, H-4, H-5), 7.43—7.18 (3H,
m, H-6, H-7, H-8), 5.97 (1H, d, Jꢂ9.9 Hz, H-3).
The Diels–Alder reactions of ortho-quinones previously
reported have been essentially performed with carbodienes.
Recently, our group reported the first examples of [4ꢀ2] cy-
cloaddition of ortho-benzofurandione15) and ortho-indolo-
quinone16) towards 1-azadienes. Thus the ortho-benzofuran-
dione reacts as a carbodienophile and ortho-indoloquinone
can react either as a carbodienophile or as heterodienophile.
In continuation of this work focused on heterocyclic
ortho-quinones we planned to investigate the chemical be-
haviour of ortho-carbazolequinones 3 and 7 towards carbodi-
enes and 1-azadienes.
9-Methyl-1,2-dihydrocarbazole-1,2(9H)-dione (4) The quinone 4 was
obtained from hydroxycarbazole 2. The crude mixture was purified by col-
umn chromatography on silica gel using CH2Cl2 as the eluent. Compound 4
was obtained as a dark green solid in 42% yield, mp 177 °C. IR (KBr) cmꢁ1
:
1
1670, 1640. H-NMR (DMSO-d6) d: 7.90 (2H, m, H-4, H-5), 7.59 (1H, d,
Jꢂ8.7 Hz, H-8), 7.45 (1H, m, H-6 or H-7), 7.26 (1H, m, H-6 or H-7), 6.01
(1H, d, Jꢂ9.8 Hz, H-3), 4.01 (3H, s, CH3-9). 13C-NMR (DMSO-d6) d:
182.7, 172.4, 141.2, 138.2, 131.2, 128.6, 123.9, 123.8, 123.3, 121.9, 112.7,
The [4ꢀ2] cycloaddition between carbazolequinone 3 or 7
and 1-acetoxy-1,3-butadiene 14 was performed at reflux in 32.6. HR-MS m/z: 211.0630 (Calcd for C13H9NO2: 211.0633).
3-Hydroxy-9-ethyl-9H-carbazole (6) A solution of 3-amino-9-ethyl-
carbazole 5 (1 g, 4.76 mmol), ice (3 g) and concentrated H2SO4 (1 ml) in
water (1.5 ml) was stirred at 0 °C. Then, a cooled solution of NaNO2
(0.391 g, 5.11 mmol) in water (1 ml) was added dropwise and the stirring
dry THF and provided directly the benzocarbazolequinones
15 and 16, respectively. The reaction between 1,3-cyclopen-
tadiene 17 and carbazolequinone 3, carried out in dichloro-
methane at ꢁ10 °C for 5 h then at room temperature for 12 h
led to the stable cycloadduct endo 18. In contrast, reaction of
7 with 1,3-cyclopentadiene 17 as above gave an unstable
tetrahydro cycloadduct which was converted into the dihydro
derivative 19 after its treatment with silicagel at 40 °C (Chart
4).
was continued for 10 min. The resulting mixture was added to acidic aque-
ous solution (3 ml of concentrated H2SO4 in 2.5 ml of water) heated at re-
flux. After 5 min the reaction mixture was poured into ice water (30 ml), ex-
tracted with CH2Cl2 and dried with Na2SO4. After removing the solvent
under vacuum, the crude product was purified by column chromatography
on silica gel with CH2Cl2 as the eluent. Compound 6 was obtained as a beige
1
solid in 15% yield, mp 106 °C. IR (KBr) cmꢁ1: 3300. H-NMR (CDCl3) d:
1
8.03 (1H, d, Jꢂ7.7, 1.1 Hz, H-5), 7.54 (1H, d, Jꢂ2.3 Hz, H-4), 7.47 (1H, td,
Jꢂ8.3, 1.1 Hz, H-7), 7.38 (1H, d, Jꢂ8.3 Hz, H-8), 7.27 (1H, d, Jꢂ8.7 Hz, H-
1), 7.19 (1H, td, Jꢂ7.7, 1.1 Hz, H-6), 7.04 (1H, dd, Jꢂ8.7, 2.3 Hz, H-2),
4.85 (1H, s, OH), 4.33 (2H, q, Jꢂ7.3 Hz, CH2CH3), 1.42 (3H, t, Jꢂ7.3 Hz,
CH2CH3). Anal. Calcd for C14H13NO·0.4 H2O: C, 76.97; H, 6.37; N, 6.41.
Found: C, 77.16; H, 6.40; N, 6.23.
9-Ethyl-3,4-dihydrocarbazole-3,4(9H)-dione (7) The quinone 7 was
obtained from hydroxycarbazole 6 by oxidation with Frémy’s salt according
to the general method described above. The crude mixture was purified by
column chromatography on silica gel using CH2Cl2/MeOH (99.5 : 0.5) as the
eluent. Compound 7 was obtained as a red solid in 50% yield, mp 195 °C. IR
The stereochemistry endo of 18 was confirmed by H-
NMR NOE DIFF experiment (Chart 5). Irradiation at
3.42 ppm (H-4a) gives responses on H-11c at 4.12 ppm and
H-12 at 1.71 ppm. Irradiation at 4.12 ppm (H-11c) gives re-
sponses on H-4a and H-12. Finally, an irradiation at
1.71 ppm (H-12) gives two responses on H-4a and H-11c.
Attempted cycloadditions of ortho-carbazolequinones 3
and 7, as dienophiles, with different 1-azadienes gave a com-
plex mixture of products and failed to yield the expected
pyridocarbazolequinones, probably due to the versatile reac- (KBr) cmꢁ1: 1670, 1640. 1H-NMR (CDCl3) d: 8.09 (1H, m, H-5), 7.31—
tivity profile of ortho-quinones in Diels–Alder reactions. Po-
tentially they can react as carbodienes, heterodienes or
dienophiles.
7.15 (4H, m, H-1, H-6, H-7, H-8), 6.16 (1H, d, Jꢂ10.2 Hz, H-2), 4.14 (2H,
q, Jꢂ7.4 Hz, CH2CH3), 1.43 (3H, t, Jꢂ7.4 Hz, CH2CH3). 13C-NMR
(DMSO-d6) d: 184.7, 173.2, 143.9, 138.4, 131.9, 129.5, 126.3, 125.6, 125.5,
121.6, 113.5, 113.1, 39.3, 16.7. Anal. Calcd for C14H11NO2·0.3 H2O: C,
72.90; H, 5.07; N, 6.07. Found: C, 72.81; H, 4.90; N, 6.07.

1116
Oxidation of 3-Amino-9-ethylcarbazole 5 with Frémy’s Salt An
aqueous solution (200 ml) of Frémy’s salt (3.2 g, 11.9 mmol) and potassium
dihydrogen orthophosphate (0.16 g, 1.19 mmol) was added to a solution of
aminocarbazole 5 (1 g, 4.76 mmol) in acetone (200 ml). The reaction mix-
ture was stirred at room temperature for 1 h, extracted with CH2Cl2, dried
over MgSO4 and concentrated under vacuum. The crude residue was purified
by column chromatography on silica gel using CH3COOEt/Petroleum ether
(20 : 80) as the eluent to give compounds 12 and 13.
Vol. 52, No. 9
yellow solid in 49% yield, mp 182 °C. IR (KBr) cmꢁ1: 3260 1700, 1640. 1H-
NMR (CDCl3) d: 8.9 (1H, s, NH), 7.87 (1H, d, Jꢂ7.9 Hz, H-11), 7.55—7.20
(3H, m, H-8, H-9, H-10), 6.1 (1H, t, Jꢂ5.3, 3.0 Hz, H-2 or H-3), 5.58 (1H, t,
Jꢂ5.3, 3.0 Hz, H-2 or H-3), 4.1 (1H, dd, Jꢂ7.2, 3.8 Hz, H-11c), 3.59 (2H, s,
H-1, H-4), 3.42 (1H, dd, Jꢂ7.2, 3.8 Hz, H-4a), 1.71 (2H, s, H-12). 13C-NMR
(DMSO-d6) d: 199.1, 172.2, 140.8, 136.3, 135.2, 134.9, 129.4, 126.1, 124.6,
123.4, 121.4, 113.9, 51.5, 49.8, 49.1, 48.2, 37.4. Anal. Calcd for
C17H13NO2·0.7 H2O: C, 74.00; H, 5.26; N, 5.07. Found: C, 73.98; H, 4.89;
N, 5.23.
3-Amino-9-ethyl-1-[(9-ethyl-9H-carbazol-3-yl)imino]-1,9-dihydro-4H-
carbazol-4-one (12) Compound 12 was obtained as a dark red solid in
11-Ethyl-1,4-dihydro-1,4-methanobenzo[a]carbazole-5,6(11H)-dione
(19) Freshly distilled cyclopentadiene 17 (0.4 g, 6.06 mmol) was added
dropwise to a solution of the carbazoledione 7 (0.15 g, 0.67 mmol) in
CH2Cl2 (6 ml) stirred and cooled at 0 °C. The stirring was continued for 6 h
at 0 °C. Then, 1.5 g of SiO2 was added and the reaction mixture was stirred
for 48 h at 40 °C. The mixture was filtered and SiO2 washed with CH2Cl2.
The combined filtrates were concentrated under vacuum. Column chro-
matography of the residue, eluting with a mixture of CH2Cl2/MeOH (98 : 2)
gave compound 19 as a dark green solid in 26% yield, mp 191 °C (decomp.).
1
10% yield, mp 236 °C. IR (KBr) cmꢁ1: 3460, 3360, 1635, 1595. H-NMR
(DMSO-d6) d: 8.19 (2H, d, Jꢂ7.4 Hz, H), 7.77 (1H, d, Jꢂ7.4 Hz), 7.76 (1H,
s, H-4ꢃ), 7.68 (1H, d, Jꢂ8.5 Hz), 7.62 (1H, d, Jꢂ8.5 Hz), 7.49—7.33 (3H,
m), 7.21—7.13 (2H, m), 6.34 (2H, br s, NH2), 5.93 (1H, s, H-2), 4.96 (2H, q,
Jꢂ7.0 Hz, CH2CH3), 4.48 (2H, q, Jꢂ7.0 Hz, CH2CH3), 1.45 (3H, t,
Jꢂ7.0 Hz, CH2CH3), 1.36 (3H, t, Jꢂ7.0 Hz, CH2CH3). Anal. Calcd for
C28H24N4O·0.4 H2O: C, 76.48; H, 5.68; N, 12.74. Found: C, 76.51; H, 5.73;
N, 12.59.
IR (KBr) cmꢁ1: 1625. H-NMR (CDCl3) d: 8.15 (1H, m, Jꢂ7.9, 1.1 Hz, H-
1
3-Amino-9-ethyl-1-[(9-ethyl-4-hydroxy-9H-carbazol-3-yl)imino]-1,9-
dihydro-4H-carbazol-4-one (13) Compound 13 was obtained as a dark
blue solid in 30% yield, mp 248 °C. IR (KBr) cmꢁ1: 3500, 3380, 1625, 1585,
7), 7.34—7.25 (3H, m, H-8, H-9, H-10), 6.96 (1H, dd, Jꢂ4.9, 3.2 Hz, H-2 or
H-3), 6.82 (1H, dd, Jꢂ4.9, 3.2 Hz, H-2 or H-3), 4.45 (2H, q, Jꢂ7.4 Hz,
CH2CH3), 4.33 (1H, s, H-1 or H-4), 4.16 (1H, s, H-1 or H-4), 2.36 (2H, m,
H-12), 1.58 (3H, t, Jꢂ7.4 Hz, CH2CH3). 13C-NMR (DMSO-d6) d: 178.6,
176.4, 160.9, 151.4, 151.2, 144.4, 141.2, 138.8, 126.8, 125.6, 125.3, 121.2,
112.7, 111.3, 71.0, 52.3, 47.8, 17.1. Anal. Calcd for C19H15NO2·0.5 H2O: C,
76.49; H, 5.41; N, 4.69. Found: C, 76.56; H, 5.29; N, 4.67.
1
1550. H-NMR (DMSO-d6) d: 9 (1H, s, OH), 8.26 (1H, d, Jꢂ7.4 Hz), 8.19
(1H, d, Jꢂ7.4 Hz), 7.75 (1H, d, Jꢂ8.1 Hz), 7.57 (1H, d, Jꢂ8.1 Hz), 7.44—
7.32 (3H, m), 7.19 (1H, m), 7.14 (1H, d, Jꢂ8.5 Hz), 7.01 (1H, d, Jꢂ8.5 Hz),
6.32 (2H, br s, NH2), 6.04 (1H, s, H-2), 5.03 (2H, q, Jꢂ7.0 Hz, CH2CH3),
4.42 (2H, q, Jꢂ7.4 Hz, CH2CH3), 1.41 (3H, t, Jꢂ7.4 Hz, CH2CH3), 1.35
(3H, t, Jꢂ7.0 Hz, CH2CH3). FAB-MS m/z 449 (MꢀH)ꢀ. Anal. Calcd for
C28H24N4O2·0.4 H2O: C, 73.79; H, 5.49; N, 12.29. Found: C, 73.87; H, 5.41;
N, 12.36.
Acknowledgments We thank Pr. Houda Fillion for her encouragement
and for the help she has given us in the preparation of the manuscript.
Benzo[c]carbazole-5,6(7H)-dione (15) 1-Acetoxy-1,3-butadiene 14
(0.503 g, 4.5 mmol) in dry THF (1 ml) was added dropwise to a solution of
carbazoledione 3 (0.3 g, 1.52 mmol) in 14 ml of the same solvent. The reac-
tion mixture was stirred at reflux for 15 h. The solvent was evaporated off to
afford a residue which was purified by column chromatography on silica gel
with CH2Cl2/MeOH (95 : 5) as the eluent to give compound 15 as a black
solid in 56% yield, mp ꢄ300 °C. IR (KBr) cmꢁ1: 3320, 1710, 1680. 1H-
NMR (CDCl3) d: 12.4 (1H, s, NH), 8.29 (1H, d, Jꢂ8.3 Hz), 8.18 (1H, d,
Jꢂ7.6 Hz), 7.89 (1H, dd, Jꢂ7.5, 1.3 Hz), 7.68 (1H, td, Jꢂ7.6, 1.3 Hz), 7.44
(2H, m), 7.34 (1H, td, Jꢂ7.5, 1.0 Hz), 7.25 (1H, td, Jꢂ6.6, 1.5 Hz). 13C-
NMR (DMSO-d6) d: 181.5, 172.3, 141.0, 136.4, 135.7, 132.9, 130.6, 130.5,
128.5, 127.9, 125.6, 123.9, 123.8, 123.3, 122.2, 114.7. Anal. Calcd for
C16H9NO2·0.3 H2O: C, 76.06; H, 3.83; N, 5.54. Found: C, 76.38; H, 4.05; N,
5.55.
11-Ethylbenzo[a]carbazole-5,6(11H)-dione (16) Synthesis of com-
pound 16 was performed starting from 7 following the procedure used for
15. Compound 16 was purified by column chromatography on silica gel with
CH2Cl2/MeOH (98 : 2) as the eluent and obtained as an orange solid in 35%
yield, mp 255 °C. IR (KBr) cmꢁ1: 1690, 1630. 1H-NMR (CDCl3) d: 8.30
(1H, dd, Jꢂ6.6, 1.8 Hz), 8.16 (1H, dd, Jꢂ7.6, 1.0 Hz), 7.80 (1H, d,
Jꢂ7.9 Hz), 7.68 (1H, td, Jꢂ7.6, 1.3 Hz), 7.46 (1H, t, Jꢂ7.4 Hz), 7.40—7.28
(3H, m), 4.59 (2H, q, Jꢂ7.3 Hz, CH2CH3), 1.69 (3H, t, Jꢂ7.3 Hz, CH2CH3).
13C-NMR (DMSO-d6) d: 182.4, 174.5, 151.3, 143.6, 139.7, 136.3, 132.1,
131.2, 130.8, 129.9, 125.9, 125.82, 125.2, 121.9, 115.1, 112.4, 41.5, 15.6.
Anal. Calcd for C18H13NO2·0.25 H2O: C, 77.26; H, 4.86; N, 5.00. Found: C,
77.31; H, 4.80; N, 4.78.
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