A short route to functionalized imidazo[4,5-c]carbazoles. Synthesis of the first example of the imidazo[4,5-c]β-carboline ring system

Article abstract of DOI:10.1016/S0040-4039(01)01915-3

A new synthetic route to functionalized imidazo[4,5-c]carbazoles (4) via intramolecular electrocyclization of indolo-1,3,5-hexatriene system (3a) is described. Thermally induced ring-closure of 2-ethylcarboxylate-(4-amino-5-imidazolyl)-3-indole (3d) led t

Full text of DOI:10.1016/S0040-4039(01)01915-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8825–8828
A short route to functionalized imidazo[4,5-c]carbazoles.
Synthesis of the first example of the imidazo[4,5-c]b-carboline
ring system
Said Achab,* Khalid Diker and Pierre Potier
Institut de Chimie des Substances Naturelles, CNRS, 91 198 Gif-sur-Yvette, France
Received 11 October 2001; accepted 12 October 2001
Abstract—A new synthetic route to functionalized imidazo[4,5-c]carbazoles (4) via intramolecular electrocyclization of indolo-
1,3,5-hexatriene system (3a) is described. Thermally induced ring-closure of 2-ethylcarboxylate-(4-amino-5-imidazolyl)-3-indole
(3d) led to the previously unknown imidazo[4,5-c]b-carboline ring system (5). These heterocycles were efficiently converted into
analogs of both the marine cytotoxic agents grossularines-1 and -2 (1) and the antimicrobial alkaloid eudistomin U (2). © 2001
Elsevier Science Ltd. All rights reserved.
The carbazole and b-carboline moieties are important
structural subunits which occur as components of many
biologically interesting, natural as well as non-natural,
compounds.1
interested in developing a ready access to carbazole and
b-carboline containing analogs of both these natural
products and the antimicrobial alkaloid eudistomin U
(2).3
As part of an investigation into the synthesis of struc-
turally related derivatives of the marine cytotoxic a-car-
bolines, grossularines-1 and -22 (1, Scheme 1), we were
Previous synthesis of imidazo[4,5-c]carbazole4 has
made use of a 3-amino-carbazole derivative as starting
material, which was elaborated further into the target
Scheme 1.
* Corresponding author. Fax: 33 01 69 07 72 47; e-mail: achab@icsn.cnrs-gif.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01915-3

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heterocycle via regioselective nitration and subsequent
imidazole ring construction. In recent years, the ther-
mal- and photo-induced electrocyclizations of 1,3,5- or
1-aza-3,5-hexatrienes have provided an efficient alterna-
tive method for accessing the carbazole and b-carboline
ring systems,5 respectively. We report herein the appli-
cation of such a methodology to the 2-acrylate-3-imida-
zolylindole derivative 3a en route to the corresponding
imidazolocarbazole 4 (Scheme 1).
boronic acid cross-coupling approach8 recently
reported by Liebeskind and Srogl.
To this end, thiol ester 11 was obtained in a straightfor-
ward manner by saponification of 10 and treatment of
the resulting acid with carbonyl-diimidazole and thio-
phenol.9 The thiol ester 11 was then subjected to palla-
dium-catalyzed cross-coupling with the known
1-tosyl-3-indoleboronic acid10 31 (Scheme 4) to provide
ketone 12 in a modest 55% yield. Deprotection of 12
under standard conditions furnished the analog 14 of
grossularine-2 (1) in good yield. The analog 17 of
grossularine-1 (1) was similarly obtained through cross-
coupling with 4-benzyloxyphenylboronic acid11 28 and
subsequent deprotection of ketone 15 (Scheme 3).
The conversion of 2-vinyl-3-imadazoloindole 9 into car-
bazole 10 was first attempted. Access to compound 9
involved Stille cross-coupling of 2-formyl-3-iodoindole6
6 with imidazolostannane 7 by a route similar to that
we reported previously7 to furnish the expected imida-
zoloindole 8 in good yield.
With carbazoles 14 and 17 in hand, we then turned our
attention to the synthesis of their b-carbolines counter-
parts. Our synthetic efforts toward this end focused
initially on the transformation of oxime 3b (R1=
CHNOH, R2=H) and hydrazone 3c (R1=HCNNMe2,
R2=H), respectively, into the b-carboline ring-system
through thermal electrocyclization.12,13 Compounds 3b
and 3c failed, however, to undergo thermal electrocy-
clization, suffering instead extensive decomposition.
Wittig reaction of aldehyde 8 gave the 2-vinyl com-
pound 9 which in turn was transformed, in good yield,
into the corresponding carbazole 10 through a one-pot
two-step process involving electrocyclization followed
by in situ aromatization with MnO2 and Raney-nickel
desulfurization (Scheme 2).
Finally, conversion of ester 10 into the requisite ketones
14 and 17 was carried out by using the thiolester–
Scheme 2. Reagents and conditions: (i) 7 (1.5 equiv.), PdCl2(PPh3)2 (6 mol%), DMF, 120°C, 2.5 h, 75–80%; (ii) NaH (1.3 equiv.),
THF, (EtO)2P(O)CH2CO2Et, 0°C, 15 min, add 8 (0.55 equiv.), 0°C then rt, 2 h, 93%; (iii) NaH (1.1 equiv.), DMF, 0°C, 30 min,
PhSO2Cl (1.2 equiv.), 0°C then rt, 2 h, 71%; (iv) o-Cl2Ph, reflux, 1 h, then add MnO2 (8 equiv.), reflux, 1 h, 72%; (v) Raney-Ni
(xs), EtOH–THF (2:1), reflux, 2 h, 84%; (vi) LiOH (7 equiv.), THF:H2O:MeOH (5:2:1), rt, 5 h, 91%; (vii) CDI (1.9 equiv.), DMF,
−10°C, 2 h, then PhSH (xs), −10°C, 2 h, 58%.
Scheme 3. Reagents and conditions: (i) 31 (1.1 equiv.) CuTc (1.5 equiv.), Pd2dba3·CHCl3 (1.2 mol%), trifurylphosphine (10 mol%),
THF, 50°C, 18 h, 55%; (ii) 10% aq. KOH, THF:EtOH (2:1), reflux, 4 h; (iii) Pd/C (10%), HCO2−NH4+, EtOH, reflux, 3 h; (iv)
28 (2 equiv.), CuTc (3 equiv.), Pd2dba3·CHCl3 (3 mol%), trifurylphosphine (26 mol%), THF, 50°C, 18 h, 60%.

S. Achab et al. / Tetrahedron Letters 42 (2001) 8825–8828
8827
Scheme 4. Reagents and conditions: (i) K2CO3, MeCN, BnBr, reflux, 3 h; (ii) (n-Bu3Sn)2, PdCl2(PPh3)2, DMF, 120°C, 2 h, 57%;
(iii) 23 (1.2 equiv.), Pd(PPh3)4 (4 mol%), CuI (8 mol%), DMF, 80%, 2.5 h, 62%; (iv) Raney-Ni, H2, MeOH, rt, 2.5 h, 64%; (v)
o-Cl2C6H4, reflux, 48 h, 79%; (vi) Tf2O, pyridine, 0°C, 30 min, rt, overnight, 87%.
Accordingly, an alternative access to the imidazolo-b-
carboline ring system was sought, based on thermally-
induced ring closure of 2-ethylcarboxylate-3-(4-amino-
5-imidazolyl)-indole 25 (Scheme 4). Synthesis of 24, the
precursor of 25, was envisaged through coupling of
imidazolostannane 22 with 3-iodoindole6 23 (Scheme
4).
dazolyl)indole 24, the subsequent reduction of which
gave 4-amino derivative 25. Intramolecular ring-closure
of 25 required prolonged heating in refluxing o-
dichlorobenzene to provide pyridone 26, which was
then transformed into triflate 27 upon exposure to
triflic anhydride in pyridine. Coupling of triflate 27 with
boronic acids 28 and 31 provided the analogs 29 and
32, which upon routine deprotection furnished the
analogs 30 and 33 of eudistomin U (2) (Scheme 5).16
Protection of the known (4,5)-iodonitroimidazole14 19
by way of N-benzyl derivatives formation15 led to a
mixture of compounds 20 and 21, the purification of
which allowed efficient recovery of isomer 20 subse-
quently transformed into stannane 22.
In the course of this work we have been able to develop
a new short approach toward the functionalized imi-
dazo[4,5-c]carbazoles 10 and have, as well, achieved the
first synthesis of the previously unknown imidazolo-b-
carboline ring system 26. In addition, these heterocycles
have been successfully converted into the potentially
Cross-coupling of stannane 22 with iodoindole 23 fur-
nished the expected 2-ethylcarboxylate-3-(4-nitro-5-imi-
Scheme 5. Reagents and conditions: (i) Pd(PPh3)4 (8 mol%), K2CO3 (2 equiv.) in H2O, LiCl (2 equiv.), dioxane, reflux, 2–3 h; (ii)
HCO2−NH4+, Pd/C (10%), EtOH, reflux, 3 h, 92%; (iii) 10% aq. KOH, EtOH:THF (2:1), reflux, 2.5 h, 67%; (iv) ii on 32, reflux,
8 h, 77%.

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interesting analogs (14, 17, 30, 31) of such biologically
active natural products as grossularine-1, grossularine-2
and eudistomin U.
5. (a) Kawasaki, T.; Sakamoto, M. J. Ind. Chem. Soc. 1994,
71, 443–457; (b) see also, Mohanakrishnan, A.K.; Srini-
vasan, P.C. J. Org. Chem. 1995, 60, 1939–1946; (c)
Choshi, T.; Matsuya, Y.; Okita, M.; Inada, K.; Sugino,
E.; Hibino, S. Tetrahedron Lett. 1998, 39, 2341–2344; (d)
Pindur, U.; Adam, R. Helv. Chim. Acta 1990, 73, 827–
838.
Acknowledgements
6. Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, Y.
Chem. Pharm. Bull. 1988, 36, 2248–2252.
7. Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett. 1995,
36, 2615–2618.
One of us (K.D.) is pleased to acknowledge the CNRS
for a fellowship.
8. Liebskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260–11261.
9. Gais, H.-J. Angew. Chem., Int. Ed. Engl. 1977, 16, 244–
246.
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