Synthesis of 4-deoxycarbazomycin B: A convenient alternative

Article abstract of DOI:10.1081/SCC-100104069

4-Deoxycarbazomycin B(3) was synthesized by condensation of 4-methoxy-2,3-dimethylacetanilide (8) with bromobenzene in presence of cuprous iodide and potassium carbonate, and subsequent hydrolysis with 20% aqueous ethanolic KOH, followed by cyclisation of the resulting substituted diphenylamine (9) with palladium acetate in acetic acid.

Full text of DOI:10.1081/SCC-100104069

This article was downloaded by: [Stony Brook University]
On: 20 December 2014, At: 21:41
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number:
1072954 Registered office: Mortimer House, 37-41 Mortimer Street,
London W1T 3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
SYNTHESIS OF 4-
DEOXYCARBAZOMYCIN B: A
CONVENIENT ALTERNATIVE
Bejoy K. Chowdhury a & Shailendra Jha b
a Department of Chemistry , School of Tropical
Medicine , Calcutta, 700073, India
b Department of Chemistry , Presidency College ,
86/1 College Street, Calcutta, 700073, India
Published online: 02 Aug 2010.
To cite this article: Bejoy K. Chowdhury & Shailendra Jha (2001) SYNTHESIS OF 4-
DEOXYCARBAZOMYCIN B: A CONVENIENT ALTERNATIVE, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
31:10, 1559-1564, DOI: 10.1081/SCC-100104069
To link to this article: http://dx.doi.org/10.1081/SCC-100104069
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all
the information (the “Content”) contained in the publications on our
platform. However, Taylor & Francis, our agents, and our licensors
make no representations or warranties whatsoever as to the accuracy,
completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of
the authors, and are not the views of or endorsed by Taylor & Francis.
The accuracy of the Content should not be relied upon and should be

independently verified with primary sources of information. Taylor and
Francis shall not be liable for any losses, actions, claims, proceedings,
demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in
relation to or arising out of the use of the Content.
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONS, 31(10), 1559–1564 (2001)
SYNTHESIS OF 4-DEOXYCARBAZOMYCIN
B: A CONVENIENT ALTERNATIVE
Bejoy K. Chowdhury1 and Shailendra Jha2,
*
1Department of Chemistry, School of Tropical Medicine,
Calcutta-700073, India
2Department of Chemistry, Presidency College,
86/1 College Street, Calcutta-700073, India
ABSTRACT
4-Deoxycarbazomycin B(3) was synthesized by condensation
of 4-methoxy-2,3-dimethylacetanilide (8) with bromobenzene
in presence of cuprous iodide and potassium carbonate, and
subsequent hydrolysis with 20% aqueous ethanolic KOH,
followed
by
cyclisation
of
the
resulting
substituted diphenylamine (9) with palladium acetate in
acetic acid.
Carbozomycins A and B (1 and 2), isolated from streptoverticillium
species, are the first antibiotics with a carbazole nucleus;1,2 and carbazo-
mycin B has been found to be the most potent among the carbazomycins.3
4-Deoxycarbazomycin B (3), a key intermediate in the synthesis of carba-
zomycin B (2), has been synthesized either via the Diels-Alder reaction of
3-vinylindole,4 via the Diels-Alder reaction of fused indole a-pyrone,5
by using irontricarbonylhexadiene complex,6 or via the Japp Klingemann
reaction.7 In their reports,5,6 the authors indicated the drawbacks of the
*Corresponding author.
1559
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1560
CHOWDHURY AND JHA
classical routes to carbazoles for the synthesis of polysubstituted deriva-
tives.7 Contrary to their observations, however, we have developed
a
simple synthesis of 4-deoxycarbazomycin B (3) via palladium
actetate mediated cyclization of substituted dipheylamine8 — a method
that has been extensively used for preparation of carbazole derivatives.9
2,3-Dimenthyl phenol (4) was converted to the corresponding
amine (6)7 via the nitroso derivative (5) and its subsequent reduction
with H2S/NH3. Acetylation of (6), followed by treatment with CH3I
and NaOCH2CH3, gave (8). Condensation of bromo-benzene with
(8)10,11 was achieved at reflux at 200ꢀC in a nitrogen atmosphere for
25 h in the presence of potassium carbonate and cuprous iodide. The
gummy residue obtained after evaporation of the solvent was hydrolyzed
by refluxing it with 20% aq. ethanolic KOH for 4.5 h to give the substituted
diphenylamine (9).
Cyclodehydrogenation of (9) to 4-deoxycarbazomycin B(3) was
accomplished with palladium acetate in acetic acid reflux for 1 h. The
solvent was distilled off, the residue was dissolved in CH2Cl2, and chroma-
tographed over silica gel. From the petrol-CH2Cl2 (1:1) eluate, a solid was
obtained, which was recrystallized from benzene (caution!) and petroleum
ether, and finally purified by sublimation under reduced pressure to furnish
colorless crystals of (3). The synthesis is outlined in Scheme 1.
EXPERIMENTAL
2,3-Dimethyl-4-nitrosophenol (5)
Conc. HCl (250 mL) was added to a solution of 2,3-dimenthyphenol
(4, 61 g, 0.5 mol) in 95% ethanol (250 mL). To the cooled mixture (0ꢀC),
sodium nitrite (40 g, 0.58 mol) was added in proportions of about 5 g each.
The mixture was stirred well after each addition. The product was
transferred to a flask containing cold water. The light yellow solid that
seperated was filtered, washed with water, dried, and crystallized from

4-DEOXYCARBAZOMYCIN B
1561
Scheme 1. Reaction Conditions: a ¼ NaNO2, HCl, CH3CH2OH, 0ꢀC; b ¼ aq. NH3,
H2S; c ¼ (CH3CO)2O, H2O, heat; d ¼ CH3CH2ONa, CH3CH2OH, CH3I; e ¼ (i)
bromobenzene, fused K2CO3, CuI, 200ꢀC, 25 h; (ii) 20% aq. ethanolic KOH, reflux,
4.5 h, f ¼ palladium acetate, AcOH, reflux, 1 h.
rectified spirit to yield yellow crystals (48 g, 63.5%), m.p 184ꢀC (lit.12
m.p. 185.4ꢀ–185.8ꢀC).
4-Amino-2,3-dimethylphenol (6)
The nitroso derivative (5, 48 g) was stirred in a mixture of 28%
aqueous ammonia (400 mL) and water (500 mL). The brown solution was
filtered and H2S was passed through it when white precipitate of the amino
compound (6) was formed. The precipitate was filtered, dried, and
crystallized from ethylaetate from ethylacetate to yield colorless crystals
(33.9 g, 78%), m.p 175ꢀC (lit.13 m.p. 175ꢀC). IR: 3390 (-NH2), 3300 (-OH)
and 1600, 1555, 1500 cmꢁ1 (aromatic).

1562
CHOWDHURY AND JHA
4-Acetamido-2,3-demethylphenol (7)
4-Amino-2,3-dimethylphenol (27.4 g, 0.2 mol) was suspended in water
(100 mL) and acetic anhydride (24 mL, 0.25 mol) was added with vigorous
stirring. The mixture was warmed in a water bath for 10 m, then cooled
and the solid that seperated out was collected by filtration and washed
with cold water. The acetyl derivative (7) was crystallized twice from
methanol to yield colorless needles (30.2 g, 84%), m.p. 178ꢀC (lit.12
m.p. 179ꢀ–179.5ꢀC). IR:3310 (-NH), 3280 (-OH), 1650 (C ¼ O) and 1600,
1540, 1500 cmꢁ1 (aromatic).
4-Methoxy-2,3-dimethylacetanilide (8)
Clean sodium (3.9 g, 0.169 mol) was placed in absolute alcohol
(120 mL) in a 1-L round-bottom flask. After the dissolution of sodium,
the mixture was cooled and 4-acetamido-2,3-dimethylphenol (7) (30 g,
0.167 mol) was added. Methyl iodine (31 g, 0.218 mol) was added slowly
to the mixture through a reflux condenser. The mixture was refluxed
for 1 h and water (300 mL) was poured slowly through the condenser.
The flask was then cooled in an icebath and the crude methylated
product (8) was collected by filtration and dried. The crude product
was dissolved in water (500 mL) and washed with 1% NaOH solution
(3 Â 100 mL), followed by water (2 Â 100 mL). The ether layer was dried
over Na2SO4, filtered, and the solvent distilled off. The residue was
crystallized from ethanol to furnish colorless needles (24 g, 74%) m.p.
171ꢀC (lit.12 m.p. 169ꢀ–170ꢀC). IR: 3300 (-NH), 1652 (C ¼ O) and 1610,
1550, 1500 cmꢁ1 (aromatic).
N-(4-Methoxy-2,3-dimethylphenyl) Aniline (9)
A mixture of compound 8 (3.86 g, 0.02 mol), fused K2CO3 (5.6 g,
0.04 mol), cuprous iodide (3.8 g, 0.01 mol), and distilled bromobenzene
(10.6 mL, 0.1 mol) was refluxed in an oil bath (bath temp ꢂ 200ꢀC) under
nitrogen atmosphere for 2.5 h. The excess bromobenzene was distilled off at
reduced pressure and the organic mass was leached with hot acetone.
The gummy residue obtained by evaporation of the solvent from ether
extract was hydrolyzed by refluxing with 20% aqueous ethanolic KOH
(20 mL) for 4.5 h. It was diluted with water, alcohol distilled off, and the
reaction mixture was poured into brine (50 mL) and extracted with ether
(3 Â 100 mL). The residue from the ether extract was chromatographed over

4-DEOXYCARBAZOMYCIN B
1563
silica gel. From 5% EtOAc-petrol eluate, compound 9 was obtained as a
solid, which was crystallized from ethanol to give colorless needles (3.36 g,
74%) m.p. 117ꢀC, (lit. m.p. 118ꢀ–119ꢀC). IR: 3380 (-NH), 1600, 1545,
1500 cmꢁ1 (aromatic).
3-Methoxy-1,2-dimethylcarbazole (3)
Compound 9 (3.4 g, 0.015 mol) was refluxed with palladium acetate
(4 g) in acetic acid (25 mL) for 1 h. The reaction was monitored by TLC.
The solvent was distilled off, the residue dissolved in CH2Cl2, and chromato-
graphed over silica gel (20 g). The column was eluted with petroleum ether,
petroleum ether-CH2Cl2 (2:1, 1:1). From petroleum ether-CH2Cl2 (1:1)
eluate, a colorless solid was obtained, which on crystallization from
benzene-petroleum ether (60ꢀ–80ꢀC), furnished colorless crystals (2.15 g,
64%) m.p. 131ꢀ–132ꢀC. (lit. m.p. 129ꢀꢁ130ꢀC) of 4-deoxycarbazomycin-B
(3). 1H NMR (CDCl3): d 8.05 (d, J ¼ 8 Hz, 1H, H-5), 7.91 (bs, 1H, NH), 7.43
(s, 1H, H-4), 7.50–7.08 (m, 3H, H-6, H-7, H-8), 3.95 (s, 3H, OCH3), 2.43
(s, 3H, Ar-CH3) and 2.33 (s, 3H, Ar-CH3). IR (KBr): 3342 cmꢁ1. UV
(MeOH): 232 (log e 4.52), 251 (4.17), 262 (3.98) and 301 nm (4.15). MS:
m/z 225 (Mþ).
REFERENCES
1. Sakano, K.; Ishimaru, K.; Nakamura, S. J. Antibiotics 1980, 33, 683.
2. Sakano, K.; Nakamura, S. J. Antibiotics 1980, 33, 961.
3. Chakraborty, D.P.; Roy, S. Fortsch. der. chem. org. Naturst. 1991,
57, 71.
4. Pinder, U.; Pfeuffer, L. Hetrocycles 1987, 26, 325.
5. Moody, C.J.; Shah, P. J. Chem. Soc., Perkin Trans 1 1989, 376.
6. Knolker, H.J.; Bauermeister, M.; Pannek, J.B. Tetrahedron 1993, 49, 84.
7. Saha, C.; Chakraborty, A.; Chowdhury, B.K. Indian J. Chem. 1996,
35B, 677.
8. Abermark, B.; Eberson, L.; Jonsson, E.; Petterson, E. J. Org. Chem.
1975, 40, 1365.
9. Chakraborty, D.P.; Bhattacharyya, P. Fortsch. der chem. org. Naturst.
1987, 52, 162.
10. Hewlins, M.J.E.; Jackson, A.H.; Long, A.; Oliveira-Campos, A.M.;
Shannon, P.V.R. J. Chem. Res. 1986, (S) 292, M (2645).
11. Hall, R.J.; Marchant, J.; Oliveira-Campos, A.M.; Queiroz, M.-J.R.P.;
Shanon, P.V.R. J. Chem. Soc., Perkin Trans 1 1992, 3439.

1564
CHOWDHURY AND JHA
12. te Nijenhuis, B.; Mulder, A.C.; Berends, W. Recl. Trav. Chim. Pays.
Bas. 1980, 115, 99. Chem. Abstr., 1980, 93, 113931n.
13. Dietrich, S.F.; Friedrich, E. Justus Liebig’s Ann. Chem. 1964, 92, 671.
Chem. Abstr., 1964, 60, 10611d.
Received in the USA August 3, 2000