Indoloquinones, Part 6.13 First palladium-mediated oxidative cyclization of arylamino-1,2-benzoquinones to carbazole-3,4-quinones - Application to the total synthesis of carbazoquinocin C and (±)- carquinostatin A

Article abstract of DOI:10.1055/s-1999-2661

A highly convergent synthesis of the carbazole-3,4-quinone alkaloids carbazoquinocin C and (±)-carquinostatin A is reported using a palladium- mediated oxidative coupling of arylamines and substituted 1,2-benzoquinones.

Full text of DOI:10.1055/s-1999-2661

596
LETTER
Indoloquinones, Part 6.13 First Palladium-Mediated Oxidative Cyclization of
Arylamino-1,2-benzoquinones to Carbazole-3,4-quinones – Application to the
Total Synthesis of Carbazoquinocin C and (±)-Carquinostatin A
Hans-Joachim Knölker,* Kethiri R. Reddy
Institut für Organische Chemie, Universität Karlsruhe, Richard-Willstätter-Allee, D-76131 Karlsruhe, Germany
Fax +49(721)698-529; E-mail: knoe@ochhades.chemie.uni-karlsruhe.de
Received 22 January 1999
en route to carbazoquinocin C was very efficient. Howev-
Abstract: A highly convergent synthesis of the carbazole-3,4-
er, the heptyl side chain at C-1 was introduced subsequent
quinone alkaloids carbazoquinocin C and (±)-carquinostatin A is re-
ported using a palladium-mediated oxidative coupling of aryl-
to the cyclization with only moderate regioselectivity.13
Because of this additional step the synthesis was less con-
vergent compared to our previous iron-mediated route
which started from a fully functionalized arylamine.10 We
now devised a novel synthesis of carbazole-3,4-quinone
alkaloids which combines the advantages of both previous
approaches by using a fully functionalized 1,2-benzo-
quinone as building block and a palladium(II)-mediated
oxidative cyclization as the key-step (Scheme 1).
amines and substituted 1,2-benzoquinones.
Key words: arylamines, 1,2-benzoquinones, palladium(II) acetate,
oxidative cyclization, carbazole alkaloids
Carbazole alkaloids represent an important class of natu-
ral products.1 Therefore, several novel methodologies for
the synthesis of carbazoles were developed over the past
10 years.2,3 Furukawa et al. reported the first isolation of
carbazole-1,4-quinones from terrestrial plants.4 Recently,
carbazole-3,4-quinone alkaloids, e.g. carquinostatin A,5
the carbazoquinocins,6 and lavanduquinocin,7 were isolat-
ed from different streptomyces by Seto et al. These com-
pounds are structurally unique because they represent the
first carbazole alkaloids containing an ortho-benzoquin-
one system. The carbazole-3,4-quinone alkaloids exhibit
antioxidative activity and represent potential therapeutic
agents for the treatment of a variety of diseases initiated
by oxygen-derived free radicals. Due to their useful bio-
logical activities the carbazole-3,4-quinones became in-
teresting targets for total synthesis.8-13 Ogasawara
reported the first synthesis of carbazoquinocin A and D.8
An electrocyclic ring closure was utilized by Hibino to get
access to carbazoquinocins.9 Based on our iron-mediated
construction of the carbazole framework,3 we described
the first total syntheses of carbazoquinocin C,10 carqui-
nostatin A,11 and lavanduquinocin.12 Recently, we report-
ed a novel improved route to carbazoquinocin C via an
efficient palladium(II)-catalyzed oxidative cyclization of
an intermediate anilino-1,4-benzoquinone as key-step.13
Scheme 1
The retrosynthesis of carbazoquinocin C (1a) based on
this approach provides aniline (2a) and 4-heptyl-3-meth-
yl-1,2-benzoquinone (3a) as precursors. Carquinostatin A
(1b) should result from the coupling of 4-prenylaniline
(2b) and 4-(2-hydroxypropyl)-3-methylbenzo-1,2-quino-
ne (3b).
The veratrole 4 was already used as precursor for the iron-
mediated synthesis of 1a.10 Ether cleavage of 4 using bo-
ron tribromide afforded the catechol 5. Oxidation of 5
with o-chloranil led to the required 1,2-benzoquinone 3a.
The 1,2-benzoquinones 3 proved to be very labile. At-
tempted purification and isolation of 3 resulted to a large
extent in decomposition. Therefore, the 1,2-benzoquinone
3a was immediately transformed to the anilino-1,2-benzo-
quinone 6 by addition of 0.5 equivalents of aniline (2a) in
methanol. It is important to note that this reaction was car-
ried out under argon atmosphere and that the second
equivalent of the 1,2-benzoquinone had to be used for the
reoxidation of the addition product to the quinone. Addi-
tion of the arylamine in the air led largely to decomposi-
The palladium(II)-mediated oxidative cyclization of N,N-
diarylamines provides carbazole derivatives.14 The appli-
cation of this procedure to the cyclization of 2-arylamino-
1,4-benzoquinones affords carbazole-1,4-quinones.15 In
the presence of an excess of cupric acetate catalytic
amounts of palladium(II) acetate can be used.16 Alterna-
tively, catalytic reactions were achieved by using t-butyl
hydroperoxide as oxidant.17 We applied the palladium(II)-
catalyzed oxidative cyclization of arylamino-1,4-quino-
nes in the presence of cupric acetate to the synthesis of
benzo[b]carbazole-6,11-diones,16 carbazomycin G and
H,18 and carbazoquinocin C.13 The palladium(II)-cata-
lyzed oxidative coupling of the anilino-1,4-benzoquinone
tion. Compound
6 could be isolated and fully
characterized. The palladium(II)-mediated oxidative cy-
Synlett 1999, No. 5, 596–598 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Application to the Total Synthesis of Carbazoquinocin C and (±)-Carquinostatin A
597
Scheme 2
clization of 6 in glacial acetic acid at 55°C provided di-
rectly carbazoquinocin C (1a) in 43% yield (Scheme 2).
Lower reaction temperatures led to a decreased turnover,
while higher reaction temperatures resulted in more de-
composition. Carbazoquinocin C is now available in three
steps and 29% overall yield based on the veratrole 4.
Scheme 4
Ether cleavage of the veratrole 911 afforded the catechol
10. Oxidation of 10 using o-chloranil provided the O-
acetyl derivative of the 1,2-benzoquinone 3b, which led to
the arylamino-1,2-benzoquinone 11 by addition of 4-pre-
nylaniline (2b). The palladium(II)-mediated cyclization
of 11 using the reaction conditions as described above
provided O-acetylcarquinostatin A (12) in 62% yield (see
Experimental Procedure). Removal of the acetyl protect-
ing group by reduction with lithium aluminum hydride
transformed 12 to (±)-carquinostatin A (1b) (Scheme 4).
The present synthesis affords (±)-carquinostatin A in four
steps and 33% overall yield based on the veratrole 9.
Scheme 3
For the synthesis of carquinostatin A (1b) by the route in-
dicated in Scheme 1 we required an efficient access to 4-
prenylaniline (2b). The acid-catalyzed amino-Claisen re-
arrangement of N-prenylaniline affords 2b only as a by-
product.19 A selective synthesis of 2b was developed by
prenylation of a protected 4-bromoaniline with bis[m-bro-
mo(h3-prenyl)nickel]20 (Scheme 3). This procedure for
the regioselective introduction of the prenyl group was al-
ready used in our iron-mediated syntheses of carquinosta-
tin A11 and neocarazostatin B.21 By a modified procedure
4-bromoaniline (7) was converted to the known phthaloyl
imide 8.22 The nickel-mediated prenylation of 8 followed
by cleavage of the imide with hydrazine in methanol at
room temperature provided 4-prenylaniline (2b).
In conclusion we developed a palladium-mediated oxida-
tive coupling of arylamines and appropriately functional-
ized 1,2-benzoquinones. This novel methodology opens
up new avenues for highly convergent, short-step synthe-
ses of carbazole-3,4-quinone alkaloids.
Synlett 1999, No. 5, 596–598 ISSN 0936-5214 © Thieme Stuttgart · New York

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H.-J. Knölker, K. R. Reddy
LETTER
Experimental Procedure
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O-Acetylcarquinostatin A (12): A mixture of 11 (80 mg, 0.21
mmol) and palladium(II) acetate (52 mg, 0.23 mmol) in glacial ace-
tic acid (10 ml) was heated at 55°C for 3.5 h under argon. The reac-
tion mixture was cooled to room temperature, silica gel (1g) was
added, the glacial acetic acid was evaporated in vacuum, and the
residue was purified by filtration over a short path of silica gel
(EtOAc/MeOH, 10:1). After removal of the solvent, hexane/EtOAc
(1:1) was added to the residue. The resulting precipitate was sepa-
rated by filtration, washed with hexane/EtOAc (1:2), and dried in
vacuo to afford 12 (49 mg, 62%) as a brown solid, mp 210-211°C.
UV (MeOH): l = 231, 267, 429 nm; IR (drift): u = 3217, 1733,
1656, 1639, 1620, 1599, 1588, 1475, 1373, 1251 cm-1; 13C NMR
and DEPT (125 MHz, DMSO-d6): d = 12.13 (CH3), 17.71 (CH3),
20.08 (CH3), 20.76 (CH3), 25.54 (CH3), 33.86 (CH2), 34.08 (CH2),
69.12 (CH), 110.84 (C), 113.13 (CH), 119.32 (CH), 123.73 (CH),
125.11 (CH), 125.99 (C), 131.53 (C), 135.20 (C), 135.53 (C),
137.54 (C), 137.70 (C), 145.68 (C), 169.73 (C=O), 172.52 (C=O),
183.53 (C=O). Analysis calcd. for C23H25NO4: C 72.80, H 6.64, N
3.69; found: C 72.33, H 6.68, N 3.51.
Acknowledgement
This work was supported by the Fonds der Chemischen Industrie
and the Alexander von Humboldt Stiftung (postdoctoral fellowship
to K. R. R.).
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Article Identifier:
(3) H.-J. Knölker, Synlett 1992, 371. H.-J. Knölker, in Advances
in Nitrogen Heterocycles, Vol. 1; C. J. Moody, Ed.; JAI Press,
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1437-2096,E;1999,0,05,0596,0598,ftx,en;G02499ST.pdf
Synlett 1999, No. 5, 596–598 ISSN 0936-5214 © Thieme Stuttgart · New York