Synthesis of carbazomycin B by radical arylation of benzene

Article abstract of DOI:10.1016/j.tet.2003.12.015

Iodination of 2-methoxy-3,4-dimethyl-5-nitrophenol followed by acetylation yields (6-iodo-2-methoxy-3,4-dimethyl-5-nitrophenyl) acetate. Reduction with iron and acetic acid followed by reaction with methyl chloroformate then provides N-methoxycarbonyl-3-acetoxy-2-iodo-4-methoxy-5,6-dimethylaniline. Treatment of this substance in benzene at reflux with tributyltin hydride and a catalytic quantity of diphenyl diselenide leads to the formation of N-methoxycarbonyl-3-acetoxy-2-(2,5-cyclohexadienyl)-4-methoxy-5, 6-dimethylaniline which on exposure to phenylselenenyl bromide affords a phenylselenenyl tetrahydrocarbazole. Oxidation deselenation and rearomatization are achieved by heating with tert-butylhydroperoxide finally affording carbazomycin B after saponification.

Full text of DOI:10.1016/j.tet.2003.12.015

Tetrahedron 60 (2004) 1513–1516
Synthesis of carbazomycin B by radical arylation of benzene
*
David Crich and Sochanchingwung Rumthao
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7061, USA
Received 12 November 2003; revised 5 December 2003; accepted 5 December 2003
Abstract—Iodination of 2-methoxy-3,4-dimethyl-5-nitrophenol followed by acetylation yields (6-iodo-2-methoxy-3,4-dimethyl-5-
nitrophenyl) acetate. Reduction with iron and acetic acid followed by reaction with methyl chloroformate then provides
N-methoxycarbonyl-3-acetoxy-2-iodo-4-methoxy-5,6-dimethylaniline. Treatment of this substance in benzene at reflux with tributyltin
hydride and a catalytic quantity of diphenyl diselenide leads to the formation of N-methoxycarbonyl-3-acetoxy-2-(2,5-cyclohexadienyl)-4-
methoxy-5,6-dimethylaniline which on exposure to phenylselenenyl bromide affords a phenylselenenyl tetrahydrocarbazole. Oxidation
deselenation and rearomatization are achieved by heating with tert-butylhydroperoxide finally affording carbazomycin B after
saponification.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
fungi,5 with weak antibacterial activity.5 Accordingly, we
selected this target as a test bed for the intended chemistry.
Previous syntheses of carbazomycin B have involved (i) the
formation of a simpler carbazole skeleton followed by
introduction of the remaining functionality; (ii) Friedel–
Crafts alkylation of a functionalized aniline with the h5-
cyclohexadienylirontricarbonyl cation, followed by an
aromatizing cyclization with ‘highly active’ manganese
dioxide,6 and (iii) a radical cyclization approach employing
an N-cyclohexadien-3-yl-o-bromoaniline.7 The synthesis
that we describe here differs significantly from the precedent
in so far as one ring is derived directly from benzene with no
prior functionalization, adjustment of oxidation state, or
complexation to a metal required.
Benzeneselenol catalyzes the stannane-mediated addition of
aryl radicals to benzene with the predominant formation of
3-aryl-1,4-cyclohexadienes.1 When the aryl radical is
functionalized in the ortho-position, subsequent cyclization
reactions lead to tetrahydrocarbazoles and/or tetrahydro-
dibenzofurans depending on the nature of the functionality
employed (Scheme 1).2
2. Results and discussion
Nitrophenol 3 was readily derived from the acetate 2, whose
synthesis was previously described by Clive and
co-workers.7 Iodination of 3 with sodium iodide, iodine,
and butylamine in water afforded the iodide 4, which was
acetylated to provide 5. This was then cleanly reduced, with
iron and ferric chloride in acetic acid,8 to the aniline 6,
derivatization of which afforded the iodocarbamate 7
(Scheme 2) ready for the key radical reaction.
Scheme 1. Formation of tetrahydrocarbazoles and dibenzofurans from
benzene.
We considered that, when coupled to a suitable
rearomatization step, this sequence would provide a ready
and direct entry into a number of carbazole alkaloids,3
especially those heavily functionalized in one benzenoid
ring yet devoid of substitution in the other. An extreme
example of the kind is carbazomycin B (1), an inhibitor of
5-lipoxygenase4 and of the growth of some phytopathogenic
In the key radical dearomatization step, an 0.05 M solution
of iodide (7) and diphenyl diselenide (20 mol%) in benzene
was treated at reflux dropwise with tributyltin hydride and
AIBN.9 After partitioning of the reaction mixture between
hexanes and acetonitrile,10 the adduct 8 was obtained by
chromatography of the acetonitrile phase in 40% yield,
together with 8% of the recovered substrate and 12% of the
Keywords: Radical; Arylation; Cyclohexadienyl; Dearomatization;
Carbazole.
*
Corresponding author. Tel.: þ1-312-996-5189; fax: þ1-312-996-2183;
e-mail address: dcrich@uic.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.015

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D. Crich, S. Rumthao / Tetrahedron 60 (2004) 1513–1516
purified by silica gel column chromatography eluting with
ethyl acetate–hexane (1:4) to afford the title phenol as
viscous yellow oil (4.28 g, 91%). 1H NMR (CDCl3): d 7.23
(s, 1H), 6.43 (br s, 1H), 3.76 (s, 3H), 2.48 (s, 3H), 2.21 (s,
3H); 13C NMR (CDCl3): d 149.1, 146.9, 146.7, 132.4,
124.4, 109.5, 61.1, 15.3, 13.1; ESIHRMS Calcd for
C9H10NO4 [M2H]2 196.0610, found 196.0609.
3.1.2. 2-Iodo-6-methoxy-4,5-dimethyl-3-nitrophenol (4).
A solution of NaI (5.03 g, 34 mmol) and iodine (4.77 g,
19 mmol) in water (17 mL) was added dropwise to a 20%
aqueous solution of BuNH2 (24 mL) and 3 (2.24 g,
11 mmol) at room temperature. The resulting brown
solution was stirred for 30 min at ambient temperature
then diluted with dichloromethane. The organic layer was
washed with water, 10% aqueous sodium thiosulphate
solution, dried, and concentrated. The residue was filtered
through a short silica gel pad and recrystallized from
EtOAc–Hex to afford the crystalline iodophenol 4 (3.00 g,
81%). Mp 178–180 8C; 1H NMR (CDCl3): d 6.26 (br s, 1H),
3.79 (s, 3H), 2.22 (s, 3H), 2.14 (s, 3H); 13C NMR (CDCl3): d
153.0, 148.4, 145.8, 132.0, 122.0, 71.3, 61.3, 15.0, 13.2;
ESIHRMS Calcd for C9H9NO4I [M2H]2 321.9576, found
321.9576.
Scheme 2. Formation of the iodocarbamate 7.
deiodinated product 9 (Scheme 3). Treatment of 8 with
phenylselenenyl bromide in dichloromethane then afforded
the tetrahydrocarbazole 10 in 74% yield. Mindful of the
earlier work of Barton and co-workers in which benzene-
seleninic anhydride was demonstrated to be an efficient
reagent for the oxidation of indolines to indoles,11,12 10 was
heated to reflux in benzene with an excess of tert-butyl
hydroperoxide resulting in the formation of the fully
aromatic species 11 in 53% isolated yield. Finally, exposure
of 11 to hot methanolic sodium hydroxide afforded
carbazomycin B (1) in 75% yield (Scheme 3) with spectral
data consistent with the literature values.7
3.1.3. 2-Iodo-3-acetoxy-4-methoxy-5,6-dimethyl nitro-
benzene (5). To a solution of iodophenol 4 (3.0 g,
10.6 mmol) in Ac2O (3.3 g, 32 mmol) was added pyridine
(0.042 g, 0.53 mmol) and DMAP (0.195 g, 1.6 mmol) at
room temperature. The reaction mixture was stirred for 10 h
at room temperature then quenched with ice/water. The
precipitate formed was filtered off and washed with water,
then was taken up in dichloromethane and filtered through a
short silica gel pad to afford acetate 5 (3.34 g, 98%). Mp
150–151 8C; 1H NMR (CDCl3): d 3.73 (s, 3H), 2.38 (s, 3H),
2.21 (s, 3H), 2.18 (s, 3H); 13C NMR (CDCl3): d 167.7,
152.5, 151.4, 144.2, 133.9, 128.6, 81.0, 61.3, 21.0, 15.6,
13.2; ESIHRMS Calcd for C11H12NO5I[M]þ 364.9760,
found 364.9776.
3. Experimental
3.1. General
3.1.1. 2-Methoxy-3,4-dimethyl-5-nitrophenol (3). Anhy-
drous HCl in MeOH (20 mL of 7 M) was added under Ar to
acetate 27 (5.76 g, 24.0 mmol), after which the reaction
mixture was heated to 70 8C with stirring for 4 h. The
reaction mixture was cooled to room temperature, concen-
trated and the residue was diluted with EtOAc and washed
with water. The organic layer was dried, concentrated and
3.1.4. 2-Iodo-3-acetoxy-4-methoxy-5,6-dimethylaniline
(6). A solution of nitrobenzene 5 (2.58 g, 8.0 mmol) and
AcOH (1.55 mL) in EtOH (13 mL) was heated to reflux
with stirring for 10 min before iron powder (3.23 g,
Scheme 3. Completion of the synthesis.

D. Crich, S. Rumthao / Tetrahedron 60 (2004) 1513–1516
1515
58 mmol) and FeCl3·6H2O (0.13 g, 0.48 mmol) were added.
The resulting mixture was heated to reflux with stirring for
4 h before it was cooled to room temperature and
concentrated. The residue was extracted with EtOAc and
the organic layer was washed with water, brine, and dried.
Purification of the extracts by silica gel column chroma-
tography eluting with EtOAc–Hex (3:7) afforded aniline 6
(1.85 g, 79%). Mp 85–87 8C; IR (CHCl3): 3404,
phenylselenenyl-1,2,4a,9a-tetrahydrocarbazole-9-car-
boxylate (10). To a stirred solution of cyclohexadiene 8
(0.036 g, 0.10 mmol) in dichloromethane (2 mL) was added
phenylselenenyl bromide (0.027 g, 0.11 mmol) at 278 8C
under Ar. The reaction mixture was allowed to come to
room temperature, then was stirred for 10 h, before it was
diluted with dichloromethane, washed with water and dried.
Concentration and purification of the crude reaction mixture
by silica gel column chromatography eluting with EtOAc–
Hex afforded the tetrahydrocarbazole 10 carbazole (0.038 g,
1
1797 cm21; H NMR (CDCl3): d 4.02 (br s, 2H), 3.65 (s,
3H), 2.38 (s, 3H), 2.19 (s, 3H), 2.09 (s, 3H); 13C NMR
(CDCl3): d 168.5, 142.9, 142.6, 142.2, 131.5, 119.4, 79.1,
61.1, 21.2, 14.9, 13.1; ESIHRMS Calcd for C11H15NO3I
[MþH]þ 336.0097, found 336.0097.
1
74%); IR (film): 1770, 1715, 1457, 1194 cm21; H NMR
(CDCl3): d 7.58 (d, J¼6.8 Hz, 2H), 7.26–7.19 (m, 3H),
5.88–5.86 (m, 1H), 5.73–5.69 (m, 1H), 4.80 (dd, J¼7.0,
11.6 Hz, 1H), 4.06 (br s, 1H), 3.82 (s, 3H), 3.67 (s, 3H), 3.31
(dt, J¼5.4, 11.2 Hz, 1H), 2.31 (s, 3H), 2.35–2.25 (m, 2H),
2.18 (s, 3H), 1.98 (s, 3H); 13C NMR (CDCl3): d 168.4,
155.8, 148.0, 138.6, 136.9, 136.0, 133.8, 131.1, 129.3,
128.9, 128.6, 128.1, 127.9, 127.0, 123.5, 66.9, 61.2, 53.3,
43.9, 40.8, 32.2, 23.0, 17.3, 13.1; ESIHRMS Calcd for
C25H27NO5SeNa [MþNa]þ 524.0952, found 524.0970.
3.1.5. N-Methoxycarbonyl-2-iodo-3-acetoxy-4-methoxy-
5,6-dimethylaniline (7). To a solution of aniline 6 (0.78 g,
2.6 mmol) in pyridine (4.2 g, 53.2 mmol) was added
dropwise methyl chloroformate (0.38 g, 4.0 mmol) at 0 8C
under Ar. The reaction mixture was stirred for 4 h at room
temperature then diluted with water and extracted with
EtOAc. The organic layer was washed with water, 20%
CuSO4 solution, dilute HCl, brine, and dried. Concentration
of the extracts and purification by silica gel column
chromatography eluting with EtOAc–Hex (2:3) afforded
carbamate 7 (0.93 g, 89%). Mp 119–121 8C; IR (CHCl3):
3450, 1783 cm21; 1H NMR (CDCl3): d 6.29 (br s, 1H), 3.77
(br s, 3H), 3.71 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H), 2.19 (s,
3H); 13C NMR (CDCl3): d 168.2, 154.9, 149.7, 143.3,
135.6, 133.1, 132.5, 77.4, 61.0, 53.0, 21.1, 16.6, 13.3;
ESIHRMS Calcd for C13H15NO5I [M2H]2 391.9995,
found 391.9995.
3.1.8. Methyl 4-acetoxy-3-methoxy-1,2-dimethyl-carba-
zole-9-carboxylate (11). To a solution of selenide 10
(0.047 g, 0.093 mmol) in benzene (2 mL) was added 70%
t
aqueous BuOOH (0.047 mL, 0.5 mmol) at room tempera-
ture. The reaction mixture was heated to reflux with stirring
for 2.5 h, then was cooled and concentrated. The crude
reaction mixture was purified by silica gel column
chromatography eluting with EtOAc–Hex (3:7) to afford
carbazole 11 (0.017 g, 53%); IR (film): 1770, 1738,
1
1194 cm21; H NMR (CDCl3): d 8.08 (d, J¼7.2 Hz, 1H),
7.83 (d, J¼7.6 Hz, 1H), 7.43 (t, J¼7.6 Hz, 1H), 7.32 (t,
J¼7.6 Hz, 1H), 4.03 (s, 3H), 3.81 (s, 3H), 2.52 (s, 3H), 2.37
(s, 3H), 2.32 (s, 3H); 13C NMR (CDCl3): d 168.6, 153.1,
146.9, 140.4, 135.9, 135.7, 130.9, 126.9, 124.6, 124.1,
123.6, 121.2, 118.8, 115.4, 61.1, 53.8, 20.8, 18.0, 13.2;
ESIHRMS Calcd for C19H19NO5Na [MþNa]þ 364.1161,
found 364.1165.
3.1.6. N-Methoxycarbonyl-2-(2,5-cyclohexadienyl)-3-
acetoxy-4-methoxy-5,6-dimethylaniline (8) and N-Meth-
oxycarbonyl-5-acetoxy-4-methoxy-2,3-dimethylaniline
(9). To a stirred solution of iodide 7 (0.120 g, 0.31 mmol)
and diphenyl diselenide (0.019 g, 0.06 mmol) at reflux in
benzene (6.0 mL) under Ar was added a solution of Bu3SnH
(0.106 g, 0.37 mmol) and AIBN (0.005 g, 0.02 mmol) in
benzene (2.5 mL) over 10 h. After the addition was
complete, the reaction mixture was further stirred for an
additional 1 h at 85 8C, then cooled to room temperature and
concentrated. The residue was partitioned between aceto-
nitrile and hexane and the acetonitrile layer was concen-
trated and purified by silica gel column chromatography
eluting with EtOAc–Hex to give the adduct 8 (0.042 g,
40%), recovered 7 (0.025 g, 8%), and the desiodo
compound 9 (0.012 g, 12%). 8: IR (film): 3387, 1767,
1716, 1505, 1457, 1185 cm21; 1H NMR (CDCl3): d 6.50 (s,
1H), 5.95–5.85 (m, 2H), 5.55 (br d, J¼8.1 Hz, 2H), 4.29–
4.22 (m, 1H), 3.71 (s, 3H), 3.68 (br s, 3H), 2.80 (m, 2H),
2.31 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H); 13C NMR (CDCl3): d
169.8, 155.8, 135.6, 131.3, 130.9, 129.6, 127.3, 126.5, 61.3,
61.1, 52.8, 52.6, 34.4, 25.9, 21.7, 20.9, 15.1, 13.7, 13.4;
ESIHRMS Calcd for C19H23NO5Na [MþNa]þ 368.1474,
found 368.1467. 9 Mp 117–119 8C; IR (film): 3320, 1768,
3.1.9. Carbazomycin B (1). A solution of carbamate (11)
(2 mg, 0.006 mmol) and NaOH (0.006 g, 0.15 mmol) in
MeOH–H2O (1:1, 1 mL) was heated with stirring in an oil
bath at 92 8C for 3 h. The methanol was then removed under
vacuum and the remaining solution was neutralized (,pH
7) with dil. HCl (1 mL) and extracted with EtOAc.
Concentration of the extracts and purification by silica gel
column chromatography eluting with EtOAc–Hex (3:7)
afforded carbazomycin B (1) (1 mg, 75%) with spectra data
comparable to the literature values;7 1H NMR (CDCl3): d
8.23 (d, J¼7.5 Hz, 1H), 7.77 (br s, 1H), 7.38–7.35 (m, 2H),
7.25–7.18 (t, J¼7.5 Hz, 1H), 6.01 (s, 1H), 3.82 (s, 3H), 2.39
(s, 3H), 2.37 (s, 3H); 13C NMR (CDCl3): d 142.4, 139.6,
138.8, 137.1, 127.3, 125.1, 123.6, 123.0, 119.8, 110.3,
109.6, 63.4, 13.6, 13.2; ESIMS Calcd for C15H15NO2Na
[MþNa]þ 241.29, found 241.29.
1
1727, 1199 cm21; H NMR (CDCl3): d 7.26 (s, 1H), 6.30
(br s, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 2.32 (s, 3H), 2.21 (s,
3H), 2.12 (s, 3H); 13C NMR (CDCl3): d 169.6, 147.4, 141.9,
132.0, 131.7, 61.2, 54.6, 20.9, 14.3, 13.9; ESIHRMS Calcd
for C13H17NO5Na [MþNa]þ 290.1004, found 290.0995.
Acknowledgements
We thank the NSF (CHE 9986200) for partial support of this
work, Dr. Mousumi Sannigrahi for the initial preparation of
2, and Professor Derrick Clive (Edmonton) for provision of
experimental details for the preparation of 2.
3.1.7. Methyl 5-acetoxy-6-methoxy-7,8-dimethyl-1-

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7. Clive, D. L. J.; Etkin, N.; Joseph, T.; Lown, J. W. J. Org.
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