Synthesis of imidazolo[5,4-b]carbazole-4,10-quinones

Article abstract of DOI:10.1055/s-2004-822923

The preparation of imidazolo[5,4-b]carbazole-4,10-quinones 9 is described. The key steps of the synthesis are selective halogen-metal exchanges on the imidazole 3 and subsequent addition to carbonyl groups of ethyl-3-formylindole- 2-carboxylate 4.

Full text of DOI:10.1055/s-2004-822923

1
306
LETTER
Synthesis of Imidazolo[5,4-b]carbazole-4,10-quinones
S
G
ynthesisof Imida
w
zolo[5,4-
b
]carbazo
é
le-4,10-qu
n
inones aëlle Desforges, Cécile Bossert, Cyril Montagne, Benoît Joseph*
Laboratoire de Chimie Organique 1, UMR-CNRS 5181, Université Claude Bernard – Lyon 1, CPE – Bâtiment 308, 43 Boulevard du
1 novembre 1918, 69622 Villeurbanne cedex, France
1
Fax +33(0)472431214; E-mail: benoit.joseph@univ-lyon1.fr
Received 15 January 2004
the resulting 4,5-diiodide 2 was N-protected in the pres-
Abstract: The preparation of imidazolo[5,4-b]carbazole-4,10-
quinones 9 is described. The key steps of the synthesis are selective
halogen-metal exchanges on the imidazole 3 and subsequent addi-
tion to carbonyl groups of ethyl-3-formylindole-2-carboxylate 4.
1
2
ence of K CO and EtOCH Cl in DMF to give 3a in 52%
2
3
2
yield. Deprotonation at position-2 of 3a with LDA (1.1
equiv), followed by addition of freshly recrystallised
13
hexachloroethane afforded 3b
(
in 95% yield
Key words: quinone, imidazole, ellipticine, metalation
Scheme 1).14
The carbazole-1,4-quinone skeleton is encountered in nat-
1
ural products such as murrayaquinone A, calothrixins A
2
3
4
and B, koeniginequinones A and B, clausenaquinone-A
and related synthetic derivatives (isoellipticine quinone,
indolocarbazole quinone, benzo[b]carbazole quinone).5
These compounds are a subject of interest because of their
remarkable biological activities such as anticancer, anti-
–7
bacterial and antimalarial effects. The pharmacological Scheme 1 Reagents and conditions: i) I (2.2 equiv), KI (2.2 equiv),
2
interest of the carbazole-1,4-quinone derivatives required NaOH aq, r.t., 1 h, 98%; ii) EtOCH Cl (1.4 equiv), K CO , DMF, r.t.,
2
2
3
4
8 h, 52%; iii) a) LDA (1.1 equiv), THF, –78 °C, 30 min; b) Cl CCCl
the development of diverse synthetic approaches (palladi-
um catalysed reactions, Diels–Alder reactions and anionic
reactions, among others).
3 3
(
1.4 equiv), THF, –78 °C, 16 h, 95%
8
–10
Selective halogen-metal exchange at position-5 of 3a was
In this report, we describe the preparation of new imida-
zolo[5,4-b]carbazole-4,10-quinones from 4,5-diiodo-imi-
dazoles 3 and ethyl-3-formylindole-2-carboxylate (4).
Our synthetic strategy was based on the ease of effecting
halogen-metal exchanges on the imidazole nucleus to pro-
duce successively two nucleophilic entities. A similar
pathway was envisaged by Gribble but failed for the syn-
1
5
initially carried out with EtMgBr (1.1 equiv) at 0 °C,
16
then indole 4 was added to the solution to afford a mix-
ture of alcohol 5a and lactone 6 in 52% combined yield
(
Scheme 2, Table 1 entry 1). Replacement of the Grignard
reagent by BuLi (1 equiv) at –78 °C led to the lone alcohol
a in 49% optimised yield.
5
5
thesis of isoellipticine quinone. This approach contrasts
with the usual way involving a ‘combined directed ortho-
metalation and cross-coupling strategy’ (Figure 1).11
Figure 1
The starting materials 3 for the current work were synthe-
sised by adapting standard methods. Commercially avail-
able imidazole 1 was diiodinated with I –KI–NaOH, and
2
Scheme 2 Reagents and conditions: i) Method A : EtMgBr (1.1
equiv), THF, 0 °C to r.t., 40 min, then 4 (1.1 equiv), r.t., 1 h; Method
B : BuLi (1 equiv), THF, –78 °C, 5 min, then 4 (1.2 equiv), THF, –78
SYNLETT 2004, No. 7, pp 1306–1308
0
3.
0
6.
2
0
0
4
°
C, 45 min; ii) EtONa (2.2 equiv), EtOH, r.t., 1 h, 85%
Advanced online publication: 10.05.2004
DOI: 10.1055/s-2004-822923; Art ID: G01904ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Imidazolo[5,4-b]carbazole-4,10-quinones
1307
Scheme 3 Reagents and conditions: i) MnO excess, CH Cl , r.t., 24 h, 7a = 66%, 7b = 84%; ii) BuLi (1 equiv), THF, –78 °C, 1 h then r.t.,
2
2
2
1
h, 8a = 48%, 8b = 52%; iii) 10% HCl aq, 1,4-dioxane, 80 °C, 2 h, 9a = 80%, 9b = 83%
Scheme 4 Reagents and conditions: i) MeLi (10 equiv), THF, reflux, 3 h; ii) NaBH excess, EtOH, reflux, 18 h, 35%
4
It is noteworthy that better coupling yield (83%, drawing Thus, treatment of 9a with MeLi and then with NaBH45
,6
not shown) was obtained when the reaction was per- afforded 1019 in 35% yield (unoptimised). Surprisingly,
formed between N-Boc-3-formylindole and imidazole 3a we were not able to remove the ethoxymethyl protecting
under the same conditions.
group in compound 10 using several acidic conditions
such as aq HCl in 1,4-dioxane, aq HBr or HBr in HOAc.
Further experiments are planned to perform this deprotec-
tion.
Alternatively, treatment of 6 with EtONa gave 5a in 85%
yield. Following the BuLi-mediated coupling methodolo-
gy, compound 5b was prepared from 3b and 4 in 50%
yield.
In summary, we have described the preparation of a new
series of compounds using an unusual strategy based on
selective halogen-metal exchanges on the imidazole
nucleus. Cytotoxic properties of compounds 8–10 will be
the subject of forthcoming investigations.20
Table 1 Yields of Compounds 5 and 6
Method
Imidazole
5 (%)
6 (%)
A
B
B
3a
3a
3b
5a (31)
5a (49)
5b (50)
6 (21)
–
–
Acknowledgment
This research work was supported by a grant from the Ministère de
l’Enseignement Supérieur et de la Recherche to C. M.
The alcohols 5 were oxidised using MnO to give the ke-
2
References
tones 7 in 66–84% yield (Scheme 3). The halogen-metal
exchange-cyclisation sequence on 7 was carried out in the
presence of BuLi in THF at –78 °C because no exchange
was observed with EtMgBr. The quinones 8 were ob-
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Pharm. Bull. 1985, 33, 4132.
(
2) Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; de Chazal,
1
7
N. M.; Kirk, K.; Saliba, K. J.; Smith, G. D. Tetrahedron
tained in moderate yields (48–52%). The in situ generat-
ed lithium ethoxide is responsible for the removal of the
Boc group. A one-pot synthesis of quinone 8a was inves-
tigated by successive addition of BuLi (1.1 equiv twice)
on 5a. Unfortunately, the reaction failed to generate more
than traces of 8a. Final EOM deprotection in acidic medi-
um afforded the final tetracyclic derivatives 9 in fair
1999, 55, 13513.
(
(
3) Saha, C.; Chowdhury, B. K. Phytochemistry 1998, 48, 363.
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1
8
yield.
(
7) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
Quinones 9 are also important intermediates in the synthe-
(8) Knölker, H.-J.; Reddy, K. R. Heterocycles 2003, 60, 1049.
sis of imidazolo analogues of ellipticine (Scheme 4).
Synlett 2004, No. 7, 1306–1308 © Thieme Stuttgart · New York

1
308
G. Desforges et al.
LETTER
(
9) (a) Poumaroux, A.; Bouaziz, Z.; Fillion, H.; Domard, M.;
H ), 7.52 (d, J = 8.0 Hz, 1 H, H ), 8.06 (d, J = 8.0 Hz, 1 H,
Ar
Ar
1
3
Giraud, J.; Pétavy, A.-F. Chem. Pharm. Bull. 1999, 47, 643.
H ), 8.28 (s, 1 H, H ), 12.99 (s, 1 H, NH). C NMR (75
Ar Ar
(
b) Bouaziz, Z.; Ghérardi, A.; Régnier, F.; Sarciron, M.-E.;
MHz, DMSO-d ): d = 14.7 (CH ), 64.2 (CH ), 74.8 (CH ),
6 3 2 2
Bertheau, X.; Fenet, B.; Walchshofer, N.; Fillion, H. Eur. J.
Org. Chem. 2002, 1834.
113.9 (CH), 115.3 (Cq), 121.4 (CH), 123.8 (Cq), 124.0
(CH), 125.9 (CH), 132.6 (Cq), 137.1 (Cq), 137.6 (Cq), 141.9
(
(
(
(
10) Bernardo, P. H.; Chai, C. L. L.; Elix, J. A. Tetrahedron Lett.
002, 42, 2939.
11) Kelly, T. R.; Zhao, Y.; Cavero, M.; Torneiro, M. Org. Lett.
000, 2, 3735.
12) Iddon, B.; Lim, B. L. J. Chem. Soc., Perkin Trans. 1 1983,
35.
13) Selected data for 3b: Yellow solid; mp 69–70 °C. IR (KBr):
(Cq), 143.8 (CH), 173.6 (Cq), 174.6 (Cq). MS (ESI): m/z =
+
2
296 [M + H ]. HRMS (CI): m/z calcd for C H N O :
1
6
14
3
3
296.1035; found: 296.1035. Compound 8b was prepared
similarly starting from 7b but was crystallised from MeOH
after chromatography. Red solid; mp >210 °C (MeOH). IR
2
–
1 1
7
(KBr): 1670, 1650 cm . H NMR (300 MHz, DMSO-d ):
6
d = 1.20–1.27 (m, 3 H, CH ), 3.65–3.73 (m, 2 H, CH ), 5.83
3
2
–
1 1
1
1
5
460, 1173, 1102 cm . H NMR (300 MHz, CDCl ): d =
(s, 2 H, CH ), 7.47–7.50 (m, 1 H, H ), 7.98–8.05 (m, 2 H,
3
2
A
r
1
3
.21 (t, J = 7.0 Hz, 3 H, CH ), 3.55 (q, J = 7.0 Hz, 2 H, CH ),
H ), 8.22 (d, J = 7.2 Hz, 1 H, H ), 9.50 (s, 1 H, NH). C
Ar Ar
3
2
1
3
.37 (s, 2 H, CH2). C NMR (75 MHz, CDCl ): d = 14.9
NMR (75 MHz, DMSO-d ): d = 14.8 (CH ), 64.6 (CH ),
3
6 3 2
(CH ), 65.0 (CH ), 77.2 (CH ), 83.2 (Cq), 94.8 (Cq), 134.3
74.0 (CH ), 114.1 (CH), 115.2 (Cq), 121.5 (CH), 123.9 (Cq),
3
2
2
2
+
35
+
(
Cq). MS (ESI): m/z = 413 [M + H ] for Cl, 415 [M + H ]
124.4 (CH), 126.2 (CH), 133.7 (Cq), 136.5 (Cq), 137.7 (Cq),
139.2 (Cq), 139.8 (Cq), 172.6 (CO), 173.9 (CO). MS (ESI):
37
for Cl.
+
35
+
37
(
14) Butz, R. H.-J.; Lindell, S. D. J. Org. Chem. 2002, 67, 2699.
15) Abarbri, M.; Thibonnet, J.; Bérillon, L.; Dehmel, F.;
Rottländer, M.; Knochel, P. J. Org. Chem. 2000, 65, 4618.
16) Using standard conditions (esterification, Vilsmeier–Haack
formylation, N-Boc-protection) the indole derivative 4 was
prepared from commercially available indole-2-carboxylic
acid in 94% overall yield.
m/z = 330 [M + H ] for Cl, 332 [M + H ] for Cl. HRMS
(CI): m/z calcd for C H ClN O : 330.0645; found:
(
1
6
13
3
3
330.0645.
(18) Compounds 9 have been characterised by H NMR, 13C
1
(
(
NMR (except carbonyl signals), IR, MS and HRMS.
1
(19) Selected data for 10: Mp >210 °C (MeOH). H NMR
(acetone-d ): d = 1.12 (t, J = 7.0 Hz, 3 H, CH ), 2.81 (s, 3 H,
6
3
17) Typical Procedure for Cyclisation: To a solution of 7a
CH ), 3.21 (s, 3 H, CH ), 3.56 (q, J = 7.0 Hz, 2 H, CH ), 5.84
3
3
2
(
131 mg, 0.2 mmol) in anhyd THF (5 mL), was dropwise
(s, 2 H, CH ), 7.15 (t, J = 7.9 Hz, 1 H, H ), 7.35 (t, J = 7.9
2 Ar
added at –78 °C a 2.24 M solution of BuLi in hexanes (103
mL, 0.2 mmol). After 1 h at –78 °C, the reaction mixture was
allowed to warm to r.t. and was then hydrolysed by a sat. aq
solution of NH Cl. The solution was extracted with CH Cl
Hz, 1 H, H ), 7.49 (d, J = 7.9 Hz, 1 H, H ), 8.15 (s, 1 H,
Ar Ar
H ), 8.29 (d, J = 7.9 Hz, 1 H, H ), 10.05 (s, 1 H, NH). 3C
1
Ar
Ar
NMR (acetone-d ): d = 11.5 (CH ), 15.0 (CH ), 15.2 (CH ),
6
3
3
3
63.6 (CH ), 76.4 (CH ), 107.0 (Cq), 111.2 (CH), 113.8 (Cq),
4
2
2
2
2
(
3 ×), the combined organic layer was dried over MgSO and
118.9 (CH), 120.6 (Cq), 123.3 (CH), 125.4 (Cq), 125.5
(CH), 128.3 (Cq), 137.5 (Cq), 142.6 (Cq), 144.7 (Cq), 146.5
(CH). MS (ESI): m/z = 294 [M + H ]. HRMS (CI): m/z calcd
4
concentrated in vacuo. The crude residue was purified by
flash chromatography on silica gel (CH Cl –MeOH, 98:2) to
+
2
2
afford quinone 8a as a red solid in 48% yield. Mp >210 °C
for C H N O: 294.1606; found: 294.1606.
1
8
20
3
–
1 1
(
MeOH). IR (KBr): 1676, 1649 cm . H NMR (300 MHz,
(20) Kuo, S.-C.; Ibuka, T.; Huang, L.-J.; Lien, J.-C.; Yean, S.-R.;
Huang, S.-C.; Lednicer, D.; Morris-Natschke, S.; Lee, K.-H.
J. Med. Chem. 1996, 36, 1447.
DMSO-d ): d = 1.12 (t, J = 7.0 Hz, 3 H, CH ), 3.58 (q, J =
6
3
7
.0 Hz, 2 H, CH ), 5.75 (s, 2 H, CH ), 7.28–7.38 (m, 2 H,
2
2
Synlett 2004, No. 7, 1306–1308 © Thieme Stuttgart · New York