Synthesis of naphthopyrrolo[3,4-c]carbazoles

Article abstract of DOI:10.1016/S0040-4039(01)01308-9

New naphthocarbazoles 1 were built from protected 3-(3-indolyl)-4-bromo-N-methylmaleimide in four steps using palladium-catalysed cross-coupling reactions such as Suzuki reaction of 3-methoxy-2-boronic acid and Heck cyclisation of triflate.

Full text of DOI:10.1016/S0040-4039(01)01308-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7025–7028
Synthesis of naphthopyrrolo[3,4-c]carbazoles
Sylvain Routier,* Ge´rard Coudert and Jean-Yves Me´rour
Institut de Chimie Organique et Analytique associe´ au CNRS, BP 6759, 45067 Orle´ans Ce´dex 02, France
Received 29 June 2001; accepted 20 July 2001
Abstract—New naphthocarbazoles 1 were built from protected 3-(3-indolyl)-4-bromo-N-methylmaleimide in four steps using
palladium-catalysed cross-coupling reactions such as Suzuki reaction of 3-methoxy-2-boronic acid and Heck cyclisation of triflate.
© 2001 Elsevier Science Ltd. All rights reserved.
granulatum’ showed strong activity as G2 checkpoint
inhibitors in the cell cycle due to the presence of two
compounds granulatimide III and isogranulatimide IV
(Fig. 1).3,4
Indolocarbazoles represent an important class of anti-
tumour antibiotics.1,2 Rebeccamycin I weak inhibitor of
topoisomerase I and staurosporin II a non-specific
protein kinase C (PKC) inhibitor are the most represen-
tative compounds of this family. Recently it has been
reported than extracts of Brazilian ascidian ‘Didemnum
These compounds, even if they lack the second indole
unit which is replaced by an imidazole moiety, are
potential candidates for cancer treatment. Numerous
potent aryl and heteroarylpyrrolocarbazoles of type V
have also been described (Fig. 2).5
Common methods to construct symmetric or non-sym-
metric bisindolylmaleimides employed indolyl Grignard
reagents in reaction with dibromomaleimides.6–8
Direct formation of the maleimide framework through
reaction of indole-3-acetimidate9 or by oxidative cou-
pling of indolyl acetate dianion10,11 have been used.
Generation of the second indole moiety via nitrene
insertion,12,13 use of 2,2%-bisindole and diazolactam14 or
dimethyl acetylene dicarboxylate15 were also tested as
alternative approaches to indolocarbazoles. By contrast
the use of palladium-catalysed cross-coupling reactions
in the construction of indolocarbazoles is scarcely
Figure 1.
* Corresponding author. Tel.: (33) 2.38.49.48.53.; fax: (33) 2.38.41.72.
81; e-mail: sylvain.routier@univ-orleans.fr
Figure 2.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01308-9

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S. Routier et al. / Tetrahedron Letters 42 (2001) 7025–7028
described;5 Suzuki reaction of triflate derivative with
Boronic acid 5 gave better results than the stannyl
derivative 6 in the cross-coupling reaction. Suzuki reac-
tion was performed by heating for 12 h the boronic acid
5 (1.5 equiv.), compounds 2, or 4 and palladium acetate
(10%) at 100°C in dioxane in the presence of
triphenylphosphine (20%) and potassium carbonate (2
equiv.). The non-similar behaviour of compounds 3 and
4 could be explained by the cleavage of the Boc protec-
tive group observed in all cases. This reaction was
inhibited by this cleavage (entries 5 and 9; yields 54 or
55% for 7). The benzenesulfonyl protective group was
not affected by conditions of the reaction. The coupling
reaction of 5 with compound 3 was more efficient (2 h
compared to 12 h) and the yield for 8 was up to 80%
(entry 7).
3-indoleboronic acid has been reported.16
The huge synthetic effort developed in this area
prompted us to report our own work about new series
of related derivatives 1 lacking an indolo group but
containing a naphtho group. The well-known indole/
naphthalene bioisostery,17 and the exploration of the
DNA intercalative binding properties18 prompted us to
replace the indole by a naphthalene group.
For the first time, introduction of the naphthalene
group on compounds 2, 3 and 4 was carried out using
the 3-methoxynaphthalene-2-boronic acid
5 or 3-
methoxy-2-trimethylstannyl naphthalene 6 (Scheme 1).
These compounds were obtained by regioselective lithi-
ation of 2-methoxynaphthalene using n-BuLi19 followed
by addition of the appropriate electrophile. Thus
trimethylborate afforded compound 5 in 78% yield
after hydrolysis and trimethylstannylchloride gave com-
pound 6 in 95% yield.
Deprotection of the hydroxy group was performed with
BBr3 in dichloromethane either on 7 or 8 (Scheme 2).
The hydroxy derivatives 10 and 11 were obtained in 72
and 98% yield, respectively. These compounds were
then converted into triflates 12 and 13, respectively, in
88 and 98% yield by reaction with triflic anhydride in
the presence of triethylamine at room temperature for 3
h. Treatment of 12 with Boc2O in THF at room
temperature gave 14 in 81% yield.
Optimisation of the cross-coupling reaction was per-
formed on 220 with the stannyl derivative 6 in dioxane
using Pd(PPh3)4 as catalyst and CuI or LiCl as addi-
tives (Table 1). Addition of CuI gave a poor yield of 7
(10%) even by changing the solvent and the amount of
6. LiCl instead of CuI increased the yield from 10 to
53%. The same behaviour (entries 3 and 5 compared to
entries 8 and 9) was observed with the Boc derivative
4.20 Use of Pd2(dba)3 as catalyst and triphenylarsine did
not improve the yield of the coupling reaction despite
the increase of the amount of catalyst (entry 6).
The final key-step of the synthesis was the cyclisation of
12–14 into 1. Numerous methods to perform this reac-
tion have been reported for indolocarbazoles with limi-
tations.21 Recently, intramolecular cyclisation of
bisindole maleimides was performed using phenylio-
dine(III)diacetate (PIFA), but this approach was unsuc-
cessful with a naphthalene group.22
Scheme 1. Reagents and conditions: (a) C6H5SO2Cl, NaH, THF, 0°C then rt, 80%.
Table 1. Stille and Suzuki cross-coupling reactions of derivatives 2–4
Entry
Reactant
(equiv.)
Coupling agent
Conditionsa
Product (yield
%)
1
2
3
4
5
6
7
8
9
2 (1.3)
2 (1.3)
2 (2.0)
2 (1.3)
2 (1.5)
2 (1.3)
3 (1.5)
4 (1.3)
4 (1.5)
6
6
6
6
5
6
5
6
5
Pd(PPh3)4 10%, CuI 20%, dioxane, 12 h
Pd(PPh3)4 10%, CuI 20%, DMF, 12 h
Pd(PPh3)4, 10%, CuI 20%, DMF, 12 h
Pd(PPh3)4 10%, LiCl (3 equiv.), dioxane, 12 h
Pd(OAc)2 10%, PPh3 20%, K2CO3, 100°C, dioxane/water, 12 h
Pd2(dba)3 30%, AsPh3 40%, LiCl (3 equiv.), K2CO3, dioxane/water, 24 h
Pd(OAc)2 10%, PPh3 20%, K2CO3, dioxane/water, 2 h
Pd(PPh3)4 10%, CuI 20%, dioxane, 10 h
7 (10)
7 (10)
7 (10)
7 (53)
7 (55)
7 (56)
8 (80)
9 (12)
7 (54)
Pd(OAc)2 10%, PPh3 20%, K2CO3, dioxane/water, 12 h
a Reactions at 100°C.

S. Routier et al. / Tetrahedron Letters 42 (2001) 7025–7028
7027
Scheme 2. Reagents and conditions: (a) BBr3 (6 equiv.), CH2Cl2, 0°C to rt, 1 h; (b) Tf2O (3 equiv.), NEt3 (3.1 equiv.), THF, 0°C
to rt, 3 h; (c) Boc2O (2 equiv.), THF, rt, 3 h, 81%; (d) see Table 2; (e) TBAF, THF, reflux, 2 h.
Table 2. Intramolecular cyclisation
Entry
Compound
Solvent
Time (h)
T (°C)
Pd(OAc)2 (%)
Yield of 15 or 16 (%)
Yield of 1 (%)
1
2
3
4
5
12
14
13
13
13
DMA
12
7
16
72
3
100
100
100
100
100
10
10
10
30
100
–
40
10
51
63
91a
Dioxane
Dioxane
Dioxane
Dioxane
20
10
–
–
a After TBAF treatment.
Attempts for this cyclisation via a Heck reaction are
summarised in Table 2. This reaction was performed
using Pd(OAc)2 as catalyst, NaOAc as base (2 equiv.)
and Bu4NCl (1 equiv.) as transfer agent. The lack of
protective group on the nitrogen atom stopped the
coupling reaction as described for Stille or Suzuki
reactions. The phenylsulfonyl group which partially
survive the experimental conditions afforded a mixture
of cyclised compounds 15 and 1 (entry 3). Increasing
the amount of palladium acetate, decreases reaction
time (entries 4 and 5) and so gave a higher yield of the
required cyclised derivative 15, which was then con-
verted into 1 by TBAF treatment.
4. Terpin, A.; Winklhofer, C.; Schumann, S.; Steglich, W.
Tetrahedron 1998, 54, 1745–1752.
5. McCort, G.; Duclos, O.; Cadilhac, C.; Guilpain, E. Tet-
rahedron Lett. 1999, 40, 6211–6215.
6. Brenner, M.; Rexhausen, H.; Steffan, B.; Steglich, W.
Tetrahedron 1988, 44, 2887–2892.
7. Steglich, W.; Steffan, B.; Kopanski, L.; Eckhardt, G. E.
Angew. Chem., Int. Ed. Engl. 1980, 19, 459.
8. Faul, M. M.; Sullivan, K. A.; Winneroski, L. L. Synthesis
1995, 1511–1516.
9. Bit, R. A.; Crackett, P. H.; Harris, W.; Hill, C. H.
Tetrahedron Lett. 1993, 34, 5623–5626.
10. Bergman, J.; Pelcman, B. Tetrahedron Lett. 1987, 28,
4441–4444.
This result indicated a non-catalytic reaction such as
described when indolocarbazoles were built using a
large excess of catalyst to perform the final intramolec-
ular cyclisation.21,23 Treatment of compound 13 with 1
equiv. of palladium acetate for 2 h in dioxane followed
by a treatment of the crude product by TBAF for 3 h,
afforded exclusively compound 124 in 91% global yield.
11. Bergman, J.; Koch, E.; Pelcman, B. J. Chem. Soc., Perkin
Trans. 1 2000, 2609–2614 and references cited therein.
12. Lowinger, T. B.; Chu, J.; Spence, P. L. Tetrahedron Lett.
1995, 36, 8383–8686.
13. Adeva, M.; Buono, F.; Caballero, E.; Medarde, M.;
Tome´, F. Synlett 2000, 832–834.
14. Wood, J. L.; Petsch, D. T.; Stoltz, B. M.; Hawkins, E.
M.; Elbaum, D.; Stover, D. R. Synthesis 1999, 1529–
1533.
15. Pindur, U.; Kim, Y.-S.; Schollmeyer, D. Heterocycles
1994, 38, 2267–2276.
In this paper we have described a straightforward and
efficient preparation of a new naphthocarbazole. The
reactivity of both the maleimide moiety and the free
nitrogen atom are under progress.
16. Neel, D. A.; Jirousek, M. R.; McDonald, III, J. H.
Bioorg. Med. Chem. Lett. 1998, 8, 47–50.
17. Yous, S.; Andrieux, J.; Howell, H. E.; Morgan, P. J.;
Renard, P.; Pfeiffer, B.; Lesieur, D.; Guardiola-Lemaˆıtre,
B. J. Med. Chem. 1992, 35, 1484–1486.
References
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19. Nakano, Y.; Imai, D. Synthesis 1997, 1425–1428.
20. Brenner, M.; Rexhausen, H.; Steffan, B.; Steglich, W.
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S. Routier et al. / Tetrahedron Letters 42 (2001) 7025–7028
21. Ohkubo, M.; Nishimura, T.; Jona, H.; Honma, T.; Mor-
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addition of water (30 mL) and extraction with CH2Cl2
(150 mL), the organic layers were washed with brine (50
mL), dried under Na2SO4, filtered and the solvents were
removed under reduced pressure. Product 1 was precipi-
tated using EtOAc, filtered, washed with EtOAc and
dried (457 mg, 91%): mp 250°C (dec.); IR (KBr, cm−1) w
23. Ohkubo, M.; Nishimura, T.; Jona, H.; Honma, T.; Ito,
S.; Morishima, H. Tetrahedron 1997, 53, 5937–5950.
24. Synthesis of 1: A solution containing compound 13 (1 g,
1.56 mmol), Bu4NCl (433 mg, 1.56 mmol), NaOAc (256
mg, 3.12 mmol) and triphenylphosphine (818 mg, 3.12
mmol), Pd(OAc)2 (350 mg, 1.56 mmol) in dry dioxane (10
mL) was heated to 90°C. After 3 h, CH2Cl2 (100 mL) was
added and the solution was filtered off. The organic
layers were washed with water, dried with Na2SO4 and
the solvents were removed under reduced pressure. Dry
THF (30 mL) was then added to the crude residue and a
solution of Bu4NF in THF (2 mL, 2 mmol, 1 M) was
added. The solution was heated to reflux for 1 h. After
1
1381, 1443, 1680, 1748, 2925, 3052, 3552 (NH). H NMR
(DMSO-d6) l 3.00 (s, 3H), 7.34 (t, 1H, J=10 Hz), 7.62 (t,
1H, J=7.5 Hz), 7.57–7.68 (m, 3H), 8.04 (d, 1H, J=7.5
Hz), 8.13 (d, 1H, J=10 Hz), 8.78 (d, 1H, J=10 Hz), 9.08
(s, 1H), 9.36 (s, 1H), 13.01 (br s, 1H, NH). 13C NMR
(DMSO-d6) l 25.7 (CH3), 110.2 (Cq), 112.6 (CH), 118.8
(Cq), 121.7 (CH), 121.8 (Cq), 112.2 (CH), 122.5 (Cq),
124.3 (CH), 124.9 (CH), 126.5 (CH), 127.5 (CH), 127.8
(CH), 128.9 (CH), 129.5 (Cq), 132.1 (CH), 132.4 (Cq),
132.6 (Cq), 140.0 (Cq), 140.8 (Cq), 169.9 (Cq), 170.8
(Cq). MS (IS) 351 (M+H)+.