Direct synthesis of dihydrobenzo[a]carbazoles via palladium-catalyzed domino annulation of indoles

Article abstract of DOI:10.1002/adsc.200900725

A straightforward one-step synthesis of annulated indoles via palladium-catalyzed, norbornene-mediated sequential intermolecular aryl ortho-alkylation/intramolecular indole C-H activation has been devised. This method provides an efficient route to a wide variety of substituted 6,11-dihydro-5H-benzo[a]carbazoles from readily accessible 3-bromoalkylindoles and iodoarenes.

Full text of DOI:10.1002/adsc.200900725

COMMUNICATIONS
DOI: 10.1002/adsc.200900725
Direct Synthesis of Dihydrobenzo[a]carbazoles via Palladium-
Catalyzed Domino Annulation of Indoles
Farnaz Jafarpoura,* and Hamideh Hazratia
a
School of Chemistry, University College of Science, University of Tehran, 14155-6455 Tehran, Iran
Fax : (+98)-21-66495291; e-mail: jafarpur@khayam.ut.ac.ir
Received: October 19, 2009; Revised: November 27, 2009; Published online: January 27, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900725.
Abstract: A straightforward one-step synthesis of
annulated indoles via palladium-catalyzed, norbor-
nene-mediated sequential intermolecular aryl
zo[a]carbazole derivatives have also found extensive
applications as photographic materials.[6] Thus, several
approaches have been developed for their syntheses
which often consist of multi-step reaction pro-
À
ortho-alkylation/intramolecular indole C H activa-
tion has been devised. This method provides an effi-
cient route to a wide variety of substituted 6,11-di-
hydro-5H-benzo[a]carbazoles from readily accessi-
ble 3-bromoalkylindoles and iodoarenes.
cesses.[1a,7] Some general methods include C-2 aryla-
ACHTUNGTRENNUNG
tion of indole-3-carbaldehydes followed by light- and
base-assisted cyclization reactions,[8] a merged direct-
ed ortho and remote metalation-Suzuki–Miyaura
cross-coupling strategy[9] and Fischer indolization of
a-tetralones in the presence of suitable protic or
Lewis acids.[10] However, these reactions often suffer
from the need for the synthesis of complex starting
materials, prior functionalization of the heteroarene,
harsh reaction conditions and low yields. One might
therefore expect that a one-step, straightforward and
generally applicable reaction protocol for the con-
Keywords: benzo[a]carbazoles; bromoalkylindoles;
domino reactions; one-step synthesis; palladium
catalyst
Annellated indoles have attracted considerable atten- struction of this framework would find significant util-
tion as they constitute an important class of natural ity in organic synthesis.
compounds with interesting biological activities.[1]
We have recently reported an efficient and straight-
While the benzo[a]carbazoles, and benzannulated car- forward route to annulated imidazole derivatives[11]
bazoles in general, are rarely found as natural prod- based on a previously reported palladium-catalyzed/
ucts, these structural motifs have elicited considerable norbornene-mediated sequential aromatic alkylation/
biological attention. For instance, compounds of type aryl-heteroaryl coupling reaction.[12] Herein, we set
1 show antitumor (leukemia, renal, colon)[2] and anti- out to explore the possibility of this methodology to
inflammatory[3] activities. Simple benzo[a]carbazoles construct dihydro-5H-benzo[a]carbazole derivatives
(Scheme 1) have been shown to bind to estrogen re- via direct C-2 arylation of 3-bromoalkylindoles.
ceptors and inhibit the growth of mammary tumors in
The approach involved the use of readily accessible
rats.[4] Furthermore, dihydrobenzo[a]carbazole deriva- 3-(2-bromoethyl)-indoles and iodoarenes, so that an
tives of type 2 have been identified as a novel agonist intramolecular direct C-2 arylation of the indole can
of the human thrombopoietin (Tpo) receptor.[5] Ben- follow ortho alkylation of an aryl iodide, forming two
carbon-carbon bonds from two carbon-hydrogen
bonds in a one-step process. This protocol takes ad-
vantage of readily available indole and aryl building
blocks, regioselectivity for indole C-2 functionaliza-
tion and one-step construction of benzo[a]carbazole
building blocks.
To test the feasibility of this reaction, we initially
examined the reaction of bromoalkylindole 3 with 5-
nitro-2-iodotoluene 4 under various reaction condi-
tions. To this end different palladium sources and li-
Scheme 1. Benzo[a]carbazole derivatives with biological ac-
tivities.
Adv. Synth. Catal. 2010, 352, 363 – 367
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
363

Farnaz Jafarpour and Hamideh Hazrati
COMMUNICATIONS
gands were examined. While with PdCl2 and PdACHTUNTRGNEUNG(dba)2 due to the elimination of hydrogen bromide from the
low yields of the desired product were obtained, use bromoalkyl tether in the presence of Cs2CO3. We
of Pd(OAc)2 resulted in higher yields. A ligand screen were pleased to find that, under the optimized reac-
revealed that trialkylphosphines such as tricyclohexyl- tion conditions of bromoalkylindole 3 (0.6 mmol,
phosphine and its HBF4 salt gave inferior reactivity in 3 equiv.), iodoarene 4 (0.2 mmol, 1 equiv.), Pd(OAc)2
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
this annulation reaction. Better results were obtained (10 mol%), TFP (22 mol%), Cs2CO3 (0.4 mmol,
with dppe, PPh3 and TFP. Screening the ratios of 2 equiv.) and norbornene (0.4 mmol, 2 equiv.) in
starting materials revealed that lowering the amount CH3CN (0.1M) at 1108C in a sealed tube for 24 h, the
of bromoalkylindole 3 to 2 equivalents resulted in a construction of the fused tricyclic heterocycle 5 was
lower yield of the expected annulated heterocycle. feasible in 63% yield (Table 1, entry 1). We next used
The large excess amount of this partner was necessary these optimal reaction conditions to investigate the
Table 1. Annulation of indoles via Pd-catalyzed, norbornene-mediated domino reaction.[a]
Entry
1
Substrate
Aryl Iodide
Product
Yield [%][b]
63
2
3
4
5
6
7
3
3
3
3
3
3
76
50
60
35
46
61[c]
8
6
59
364
asc.wiley-vch.de
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 363 – 367

Direct Synthesis of Dihydrobenzo[a]carbazoles
Table 1. (Continued)
Entry
Substrate
Aryl Iodide
Product
Yield [%][b]
9
18
8
62
10
11
18
18
10
58
14
10
45[c]
12
35
[a]
All reactions were run under the following conditions: PdACHTNUGRTNEUNG(OAc)2 (10 mol%), TFP (22 mol%), Cs2CO3 (2 equiv.), norbor-
nene (2 equiv.) and bromoalkylindole (3 equiv.) in CH3CN (0.1M) were heated in a sealed tube at 1108C for 24 h.
Isolated yields.
As the product was contaminated by an uncharacterized impurity, an approximate yield is given and full characterization
was not obtained for this product.
[b]
[c]
scope of the reaction with a range of aryl iodides. The
It was also desirable to test whether substituted
results showed that a variety of substituents were tol- indole derivatives could be applied in the reaction. In
erated under the reaction conditions. The para-fluoro- this regard, 3-(2-bromoethyl)-5-methoxy-1-methylin-
substituted iodoarene 6 resulted the annulated indole dole 18 was employed. While with the ortho- and
7, a good partner for further functionalizations, in para-nitro-substituted coupling partners 10 and 14,
high yield, while the ortho-substituted one 12 afforded comparable results were obtained, the para-carbonyl
product 13 in only 35% yield (the acyclic ortho-alky- substituted one 8, resulted in higher yield of the annu-
lated product was the major one) (Table 1, entries 2 lated product 20 (Table 1, entries 9–11).
and 5). We next expanded the scope of aryl iodides to
Finally, we examined the scope of the reaction with
include carbonyl groups. The para-carbonyl-substitut- the free NH bromoalkylindole 23. The reaction of the
ed iodoarene 8, gave a satisfactory result (50%, substrate 23 with iodoarene 10, resulted in lower
Table 1, entry 3), however, the ortho-substituted one, yields compared to the N-protected one, which is at-
was not tolerated under the reaction conditions. This tributed to catalyst poisoning (Table 1, entry 12).
was in accord with the results previously reported.[13a]
The possible mechanism for the first step, the
With ortho- and para-substituted nitro coupling part- ortho-alkylation of iodoarene, is based upon the find-
ners, good to moderate yields of the desired products, ings of Catellani.[13] The intermolecular ortho-alkyla-
11 and 15, were obtained (60% and 46%, respectively, tion step likely proceeds through a Pd(II)-Pd(IV) cat-
Table 1, entries 4 and 6). Nitro- and methyl-substitut- alytic cycle and generates heteroaryl-tethered arylpal-
ed iodoarene partners 4 and 16 gave comparable re- ladium(II) intermediate 25 (Scheme 2). In accord
sults (63% and 61%, respectively, Table 1, entries 1 with these findings, when the reaction was carried out
and 7). We next investigated the scope of the reaction in the absence of norbornene, no ortho-alkylated aryl
with more sterically encumbered aryl iodides. With an iodide was isolated. The reaction products consisted
ortho-blocking CF3 group, only a low yield of the de- of C-2 arylated indole and traces of the biaryl by-
sired product was obtained, presumably due to steric product.
À
hindrance between the C F bonds of the CF3 group
and C H bonds of N-Me unit (data not reported in moalkylindole 3, no acyclic ortho-inserted products
Table 1).
Excluding the reaction of iodoarene 12 with bro-
À
were isolated in these reactions which is in accord
Adv. Synth. Catal. 2010, 352, 363 – 367
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
365

Farnaz Jafarpour and Hamideh Hazrati
COMMUNICATIONS
Scheme 2. Electrophilic aromatic substitution mechanism for the intramolecular direct arylation of p-excessive heteroarenes.
with a subsequent direct C-2 arylation of indoles Experimental Section
under the optimized reaction conditions. There are
three reaction mechanisms that may rationalize the Typical Experimental Procedure for the Annulation
palladium-catalyzed direct C-2 arylation of indoles: of Indoles
(1) carbometalation,[14] (2) non-electrophilic metala-
A vial equipped with a stir bar was charged with iodoarene
tion of the 2-position,[15] and (3) electrophilic metala-
(0.200 mmol,
1.0 equiv.),
3-(2-bromoethyl)indole
tion-migration.[16]
(0.600 mmol, 3.0 equiv.), tri-2-furylphosphine (0.044 mmol,
22 mol%), Pd(OAc)2 (0.020 mmol, 10 mol%), norbornene
Sames recently provided a rational explanation for
the high C-2 selectivity in the palladium-catalyzed ar-
ylation of indoles through kinetic studies and a Ham-
mett plot.[16] The results showed that the most likely
pathway is an electrophilic substitution at the C-3 po-
sition, followed by a C-3 to C-2 palladium migration.
Exploring aryl iodides of different electronic charac-
ter, good results obtained with electron-deficient aryl
iodides (Table 1). It was suggested that electron-rich
aromatic systems stabilize Pd(II) species 25, thus re-
ducing itꢁs electrophilicity and subsequent reactivity
in the direct heteroarylation step.[12e] Therefore, we
have considered the electrophilic aromatic substitu-
tion mechanism to be the most probable one for the
intramolecular direct arylation reaction forming the
AHCTUNGTRENNUNG
(0.400 mmol, 2.0 equiv.) and Cs2CO3 (0.400 mmol,
2.0 equiv.). Dry degassed CH3CN (0.1M) was then added
and the vial was capped and further degassed. The resulting
mixture was heated in an oil bath at 1108C for 24 h, cooled
then filtered through a short plug of silica. Removal of the
solvent gave a crude mixture which was purified by flash
column chromatography (hexane/EtOAc gradient).
1,11-Dimethyl-3-nitro-6,11-dihydro-5H-benzo[a]carbazole
(5): Following the general procedure for the annulation of
indoles, 5-nitro-2-iodotoluene 4 (53.0 mg, 0.200 mmol) and
3-(2-bromoethyl)-1-methylindole 3 (143.0 mg, 0.600 mmol)
were reacted at 1108C for 24 h. The crude mixture was puri-
fied by flash column chromatography on silica gel (EtOAc/
hexane, 10%) to afford 5 as an oil; yield: 37 mg (63%);
1H NMR (400 MHz, CDCl3): d=2.65 (s, 3H, CH3), 2.87 (m,
2H), 2.93 (m, 2H), 3.69 (s, 3H, NCH3), 7.21 (ddd, J=8.4,
6.4, 1.0 Hz, 1H), 7.32 (ddd, J=8.0, 6.4, 1.6 Hz, 1H), 7.41
(dd, J=8.4, 1.6 Hz, 1H), 7.64 (dd, J=8.0, 1.0 Hz, 1H), 8.04
(d, J=2.2 Hz, 1H), 8.08 (d, J=2.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=14.1, 22.6, 31.6, 110.7, 115.0, 118.1,
119.5, 120.5, 123.4, 125.3, 132.7, 136.4, 141.3, 145.4; IR
(KBr): n=1334, 1518, 2957, 3050 cmÀ1; MS: m/z (%)=292
(M+, 44%), 221 (34), 188 (100), 142 (83), 115 (29), 73 (51);
anal. calcd. for C18H16N2O2: C 73.95, H 5.52, N 9.58; found:
C 74.09, H 5.61, N 9.47.
À
aryl N-heteroaryl bond at the 2-position of the N-
heteroaryl compound. (Scheme 2).
In summary, we have developed a straightforward
and general one-step approach to highly functional-
ized benzo[a]carbazoles using readily accessible 3-
bromoalkylindoles and iodoarenes. We have explored
the scope of domino palladium-catalyzed, norbor-
nene-mediated sequential aromatic alkylation/aryl-
heteroaryl coupling reaction for construction of these
structural motifs that are not easily accessible by con-
ventional methods. Expansion of the derived method-
ology for the construction of similar heteroaromatics
such as pyrroles and imidazoles and further function-
alization of the annulated products are under investi-
gation.
Supporting Information
Experimental procedures and characterization data for new
compounds are available as Supporting Information.
366
asc.wiley-vch.de
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 363 – 367

Direct Synthesis of Dihydrobenzo[a]carbazoles
[10] a) L. Martarello, D. Joseph, G. Kirsch, Heterocycles
1996, 43, 367–379; b) T. Okubo, R. Yoshikawa, S.
Chaki, S. Okuyamac, A. Nakazato, Bioorg. Med. Chem.
2004, 12, 3569–3580.
[11] F. Jafarpour, P. T. Ashtiani, J. Org. Chem. 2009, 74,
1364–1366.
Acknowledgements
We gratefully acknowledge the financial support of the Iran
National Science Foundation (INSF) and the University of
Tehran (27827/1/01).
[12] a) B. Laleu, M. Lautens, J. Org. Chem. 2008, 73, 9164–
9167; b) C. Blaszykowski, E. Aktoudianakis, D. Alberi-
co, C. Bressy, D. G. Hulcoop, F. Jafarpour, A. Jousha-
ghani, B. Laleu, M. Lautens, J. Org. Chem. 2008, 73,
1888–1897; c) A. Martins, ; M. Lautens, J. Org. Chem.
2008, 73, 8705–8710; d) C. Blaszykowski, E. Aktoudia-
nakis, C. Bressy, D. Alberico, M. Lautens, Org. Lett.
2006, 8, 2043–2045; e) A. Martins, D. Alberico, M.
Lautens, Org. Lett. 2006, 8, 4827–4829; f) C. Bressy, D.
Alberico, M. Lautens, J. Am. Chem. Soc. 2005, 127,
13148–13149.
[13] a) M. Catellani, F. Frignani, A. Rangoni, Angew. Chem.
1997, 109, 142–145; Angew. Chem. Int. Ed. Engl. 1997,
36, 119–122; b) M. Catellani, Top. Organomet. Chem.
2005, 14, 21; c) J. Tsuji, in: Palladium Reagents and Cat-
alysis – New Perspectives for the 21st Century, 1st edn.,
John Wiley & Sons, New York, 2004, pp 409–416;
d) M. Catellani, Synlett 2003, 298–313; e) M. Catellani,
in: Handbook of Organopalladium Chemistry for Or-
ganic Synthesis, (Eds.: E.-I. Negishi, A. de Meijere),
John Wiley & Sons, New York, 2002, pp 1479–1489;
f) M. Catellani, C. Mealli, E. Motti, P. Paoli, E. Perez-
Carreno, P. S. Pregosin, J. Am. Chem. Soc. 2002, 124,
4336–4346.
[14] a) A. P. Kozikowski, D. Ma, Tetrahedron Lett. 1991, 32,
3317–3320; b) R. Grigg, V. Sridharan, P. Stevenson, S.
Sukirthalingam, T. Worakun, Tetrahedron 1990, 46,
4003–4018.
[15] a) S. Tollari, F. Demartin, S. Cenini, G. Palmisano, P.
Raimondi, J. Organomet. Chem. 1997, 527, 93–102;
b) T. Motoyama, Y. Shimazaki, T. Yajima, Y. Naka-
bayashi, Y. Naruta, O. Yamauchi, J. Am. Chem. Soc.
2004, 126, 7378–7385; c) E. Capito, J. M. Brown, A.
Ricci, Chem. Commun. 2005, 1854–1856.
References
[1] a) H.-J. Knolker, K. R. Reddy, Chem. Rev. 2002, 102,
4303–4428; for selected examples of annulated indoles,
see: b) A. P. Kozikowski, D. Ma, J. Brewer, S. Sun, E.
Costa, E. Romeo, A. Guidotti, J. Med. Chem. 1993, 36,
2908–2920; c) R. Gastpar, M. Goldbrunner, D. Marko,
E. von Angerer, J. Med. Chem. 1998, 41, 4965–4972;
d) R. Faust, P. J. Garratt, R. Jones, L.-K. Yeh, J. Med.
Chem. 2000, 43, 1050–1061.
[2] U. Pindur, T. Lemster, Recent Res. Devel. Org. Biorg.
Chem. 1997, 33–54.
[3] D. W. Beight, M. D. Kinnick, H. Lin, J. M. Morin, M. E.
Richett, D. J. Sall, J. S. Sayer, US Patent WO
2002050034, 2002; Chem. Abstr. 2002, 137, 47114.
[4] E. Lescot, G. Muzard, J. Markovits, J. Belleney, B. P.
Roques, J. Le Pecq, J. Med. Chem. 1986, 29, 1731–
1737.
[5] a) P. B. Alper, T. H. Marsilje, D. Mutnick, W. Lu, A.
Chatterjee, M. J. Roberts, Y. He, D. S. Karanewsky, D.
Chow, J. Lao, A. Gerken, T. Tuntland, B. Liu, J. Chang,
P. Gordon, H. M. Seidel, S.-S. Tian, Bioorg. Med.
Chem. Lett. 2008, 18, 5255–5258; b) T. H. Marsilje,
P. B. Alper, W. Lu, D. Mutnick, P.-Y. Michellys, Y. He,
D. S. Karanewsky, D. Chow, A. Gerken, J. Lao, M.-J.
Kim, H. M. Seidel, S.-S. Tian, Bioorg. Med. Chem. Lett.
2008, 18, 5259–5262.
[6] S. Tomoyuki, S. Masaomi, T. Chiaki, Japanese Patent
JP 09048757, 1997; Chem. Abstr. 1997, 126, 244806d.
[7] a) D. B. Grotjahn, K. L. Dçtz, Synlett 1991, 381–390;
b) H.-J. Knçlker, H. Goesmann, C. Hofmann, Synlett
1996, 737–740; c) W. Harris, C. H. Hill, E. Keech, P.
Malsher, Tetrahedron Lett. 1993, 34, 8361–8364.
[8] C. B. de Koning, J. P. Michael, A. L. Rousseau, J.
Chem. Soc. Perkin Trans. 1 2000, 1705–1713.
[16] B. S. Lane, M. A. Brown, D. Sames, J. Am. Chem. Soc.
2005, 127, 8050–8057.
[9] X. Cai, V. Snieckus, Org. Lett. 2004, 6, 2293–2295.
Adv. Synth. Catal. 2010, 352, 363 – 367
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
367