Syntheses of indolo[3,2,1-d,e]phenanthridines and isochromeno[3,4-a] carbazoles: Palladium catalyzed intramolecular arylation via C-H functionalization

Article abstract of DOI:10.1016/j.tetlet.2011.09.018

A new synthetic route has been developed for the preparation of indolo[3,2,1-d,e]phenanthridines and isochromeno[3,4-a]carbazoles via palladium catalyzed intramolecular biaryl coupling reactions. The coupling reactions proceeded smoothly and in high yield

Full text of DOI:10.1016/j.tetlet.2011.09.018

Tetrahedron Letters 52 (2011) 6030–6034
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Tetrahedron Letters
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Syntheses of indolo[3,2,1-d,e]phenanthridines and isochromeno[3,4-a]
carbazoles: palladium catalyzed intramolecular arylation via C–H
functionalization
Ezhumalai Yamuna a, Matthias Zeller b, Karnam Jayarampillai Rajendra Prasad a,
⇑
a Department of Chemistry, Bharathiar University, Coimbatore 641 046, India
b Department of Chemistry, Youngstown State University, One University Plaza, Youngstown, OH 44555, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthetic route has been developed for the preparation of indolo[3,2,1-d,e]phenanthridines and
isochromeno[3,4-a]carbazoles via palladium catalyzed intramolecular biaryl coupling reactions. The cou-
pling reactions proceeded smoothly and in high yields under ligand-free conditions with the catalytic
system Pd(OAc)2/Cs2CO3/TBAB. Under optimized reaction conditions no halogen-reduced products were
observed.
Received 13 May 2011
Revised 30 August 2011
Accepted 4 September 2011
Available online 7 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Biaryl coupling
Intramolecular cyclization
Palladium catalyst
Indolo[3,2,1-d,e]phenanthridines
Isochromeno[3,4-a]carbazoles
The search for new methods for the construction of organic
molecules from simple and readily available starting materials is
an ongoing challenge for organic chemists. Intramolecular
aryl–aryl coupling reactions involving palladium reagents have
been used to synthesize many condensed hetero aromatic
compounds.1–6 Out of all of these coupling reactions, palladium-
catalyzed cyclization reactions have proven over the last decade
to be an extremely powerful and useful tool for the construction
of carbon–carbon, as well as carbon–heteroatom bonds.7 In partic-
ular, intramolecular biaryl coupling reactions are of considerable
interest due to their utility in the synthesis of many condensed
hetero aromatic compounds, such as indoles, quinolines, or
carbazoles.8 Among these carbazoles9 and their fused derivatives,
such as pyrido,10 pyrrolo,11 and pyranocarbazoles12 have received
considerable attention from both medicinal as well as synthetic
chemists as these compounds display a wide range of biological
activities such as anti-cancer,13 anti-HIV,14 DNA-intercalator,15 or
anti-microbial.16
other auxiliary ligands, which are often added to tailor catalyst
selectivity or to increase catalyst lifetime, as the removal of the
ligands may become problematic in the separation process.20 Over-
coming these hurdles will necessarily require the discovery and
development of new or even novel catalytic systems. However,
many palladium-catalyzed biaryl-coupling reactions proceed
under ligand-free conditions only poorly and give no or only low
product yields.21 These above mentioned observations have
prompted us to test one such reaction—a Heck type reaction—
under ligand-free conditions to improve the product yield and
undertake a study of this reaction to synthesize biologically inter-
esting heterocycles such as indolo[3,2,1-d,e]phenanthridines and
isochromeno[3,4-a]carbazoles.
The Heck precursors 9-(2-bromobenzyl)-2,3,4,9-tetrahydro-1
H-carbazol-1-ones 3a–d required for our present study were
synthesized22 in 90–95% yields by stirring 2,3,4,9-tetrahydro-1
H-carbazol-1-ones 1a–e with 2-bromobenzyl bromide 2 in dry ace-
tone in the presence of KOH. The structures of the compounds 3a
and 3d were confirmed by X-ray diffraction studies (Figs. 1 and
2, and Supplementary data). When the coupling reaction was
carried out with precursor 3a in the presence of 5 mol % of
Pd(OAc)2 as catalyst, Cs2CO3 as base, and tetrabutylammonium
bromide (TBAB) as an additive in anhydrous DMF as a solvent at
110 °C for 2 h under a nitrogen atmosphere, the 2-methyl-8H-
indolo[3,2,1-de]phenanthridin-10-ol derivative 4a was obtained
in 90% (Scheme 1).23
Although a number of protocols have been developed for the
coupling of biaryl moieties, many of them have limited applicabil-
ity in organic synthesis due to the harshness of reaction conditions,
functional group intolerance17, or high18 (or even stoichiometric)19
catalyst loading. Another problem is the use of phosphine and
⇑
Corresponding author. Tel.: +91 422 2422311; fax: +91 422 2422387.
E-mail address: prasad_125@yahoo.com (K.J. Rajendra Prasad).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.018

E. Yamuna et al. / Tetrahedron Letters 52 (2011) 6030–6034
6031
The best possible conditions for the cyclization were found
through a series of experiments using various catalysts, bases,
additives and solvents (Table 1). We found that the catalyst, base
and solvent have a profound effect on the reaction yield. The use
of PdCl2, which is mostly used in Heck type reactions, provides only
30% yield of the cyclized product 4a (Table 1, entry 3). Here, it is
pertinent to note that the additives such as TBAB play an important
role in the cyclization. Without any additives the reaction did not
occur (entries 1 and 11). The effect of base on the reaction was also
investigated. The use of KOAc as a base gave 40% of 4a in DMF (en-
try 8). Replacement of KOAc with Cs2CO3 was found to be highly
effective with the catalyst Pd(OAc)2 (entries 10 and 12) and an
excellent yield of the product was obtained in DMF (entry 13).
Other inorganic bases such as K2CO3, Ag2CO3 and organic bases like
Et3N were explored. The use of Ag2CO3 was found to be effective
(entry 7). However, with K2CO3 and Et3N, no reaction did occur
at all (entries 5 and 6). Among the several aprotic polar solvents
examined, DMF gave the highest yields. Other solvents such as
DMSO were also found to be effective, but gave lower yields (en-
tries 3, 11, and 12). The reaction also did not occur at or below
Table 1
Cyclization of 9-(2-bromobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-1-one (3) under
various conditions
Figure 1. X-ray crystal structure of compound 3a, thermal ellipsoid probability at
50%.
Entry Reactant Catalyst
10 mol %
Base
1.5 equiv
Additive
1.5 equiv
Solvent Yield
1
3
4
5
6
7
8
10
11
12
13
14
15
16
17
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
—
PdCl2
PdCl2
Cs2CO3
Cs2CO3
Cs2CO3
Et3N
K2CO3
Ag2CO3
KOAc
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
—
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
DMSO
DMF
DMF
DMF
DMF
DMF
N.R.
20
30
N.R.
N.R.
38
40
54
N.R.
67
90
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
—
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
92
N.R.
93
94
Figure 2. X-ray crystal structure of compound 3d, thermal ellipsoid probability at
50%.
N.R.—No Reaction.
Scheme 1. Synthesis of 8H-indolo[3,2,1-de]phenanthridin-10-ol.

6032
E. Yamuna et al. / Tetrahedron Letters 52 (2011) 6030–6034
Scheme 2. Synthesis of 2, 13-dihydroisochromeno[3,4-a]carbazole.
85 °C. In order to examine the versatility of this intramolecular
biaryl coupling reaction, a series of 8H-indolo[3,2,1-de]phenanthri-
din-10-ols 4a,b,d,e were synthesized under the optimized condi-
tions. Details of all reaction conditions that were checked are
given in Table 1.
The starting materials 1-hydroxy carbazoles 5a–d for another
series of coupling reactions were easily prepared24 by the reaction
of 2,3,4,9-tetrahydro-carbazol-1-ones 1a–d upon reduction with
Pd/C. Treatment of 1-hydroxy carbazoles 5 with 2-bromobenzyl-
bromide 2 in acetone in the presence of anhydrous K2CO3 under
refluxing conditions afforded the corresponding O-substituted
products 6 in high yield (Scheme 2).25 The actual coupling reaction
was first tested for 1-(2-bromo-benzyloxy)-6-methyl-9H-carba-
zole 6a. The use of bases such as Ag2CO3, KOAc or K2CO3 in DMA
gave only low yields of 7a (entries 2, 4, and 5). Our next attempt
to initiate the cyclization of 6a in presence of Pd(OAc)2, Cs2CO3
as the base, TBAB as an additive in DMA as the solvent gave the cy-
clized product 10-methyl-2,13-dihydroisochromeno[3,4-a]carba-
zole 7a in 60% yield (Table 2, entry 6). All attempts to optimize
the reactions conditions using PdCl2 gave lower yields. Therefore,
we decided to focus the optimization attempts on the Pd(OAc)2
system.
Table 2
Cyclization of 1-(2-bromobenzyloxy)-6-methyl-9H-carbazole 6 under various condi-
tions
A study of the influence of various solvents (DMF, DMSO, and
DMA) suggested that DMF is the best choice. No reaction was
found to occur below 90 °C. Switching to the mild base Cs2CO3 in
these reactions gave the desired cyclized product 7a. The best re-
sults were achieved using Cs2CO3 as the base, Pd(OAc)2 as the cat-
alyst, TBAB as an additive and DMF as a solvent at 110 °C. After 4 h
of reaction time this procedure provided a 85% yield of the cyclized
product 7a (entry 8).26 The results for all compounds 7a–d are
summarized in Table 2.
Entry Reactant Catalyst
(10 mol %)
Base
Additive
Solvent Yield
(%)
(1.5 equiv) (1.5 equiv)
1
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
PdCl2
Ag2CO3
Ag2CO3
Ag2CO3
KOAc
—
DMSO
DMA
DMF
DMA
DMA
DMA
DMSO
DMF
DMF
DMF
DMF
20
23
30
34
N.R.
50
N.R.
85
80
81
2
PdCl2
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
3
PdCl2
4
5
6
7
8
9
10
11
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3
From a mechanistic point of view, the cyclization most likely
proceeds through oxidative addition of Pd(0) to the 1-(2-bromo-
Cs2CO3
Ag2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
benzyloxy)-9H-carbazole 6 to give a
r-aryl palladium intermedi-
ate. Electrophilic attack on the aromatic ring leads to the biaryl pal-
ladium species, which after reductive elimination of palladium
affords the cyclized products 7.
82
Scheme 3. A catalytic cycle for the formation of 4.

E. Yamuna et al. / Tetrahedron Letters 52 (2011) 6030–6034
6033
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A similar catalytic cycle for the formation of the product 4 from
the substrate 3 is outlined in Scheme 3. Abstraction of halide by
Cs2CO3 leads to cationic intermediate 9 presumably stabilized by
the nitrogen atom of the tetrahydrocarbazole moiety. Cs2CO3
abstraction of a proton from 9 leads to the intermediate 11. On
subsequent enolization and dehydrogenation, the product 4 was
obtained. It has been observed that the biaryl coupling reactions
proceeded smoothly under our optimized reaction conditions and
gave good yields of the cyclized products under ligand-free condi-
tions. No halogen-reduced product was observed at all. The use of
Cs2CO3 as base seems to completely inhibit the formation of this
undesired reduced product and thus dramatically improves the
yield of the desired product 4.
In conclusion, we have developed a convenient and high yield-
ing method for the synthesis of indolo[3,2,1-d,e]phenanthridines
and isochromeno[3,4-a]carbazoles, present in many biologically
active alkaloids, by palladium-catalyzed intramolecular Heck reac-
tion under ligand-free conditions. The method is new, mild and
highly effective for the cyclization of biaryl systems, and afforded
the cyclized products in high yields. The method is likely to be
applicable for many other ring systems and hetero atomic species.
Acknowledgments
Our sincere thanks go to the Director, ISO Quality Assurance
Cell, IICT, Hyderabad, and SAIF, IIT Madras, Chennai and the Chair-
man, NMR Research Centre, IISc, Bangalore, for providing access to
their Mass and NMR spectral facilities. The diffractometer was
funded by NSF grant 0087210, by the Ohio Board of Regents grant
CAP-491, and by Youngstown State University.
19. Futagami, S.; Ohashi, Y.; Imura, K.; Hosoya, T.; Ohmori, K.; Matsumoto, T.;
Suzuki, K. Tetrahedron Lett. 2000, 41, 1063.
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Am. Chem. Soc. 2000, 122, 9127; (c) Harayama, T.; Akiyama, T.; Akamatsu, H.;
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22. General procedure for the synthesis of 9-(2-bromobenzyl)-2,3,4,9-tetrahydro-1H-
carbazol-1-one (3):
Supplementary data
To a solution of respective 2,3,4,9-tetrahydro-1H-carbazol-1-one (1, 1 mmol)
and acetone (15 mL), powdered KOH was added in ice cold condition. After few
minutes 2-bromobenzylbromide (1 mmol) was added to the solution with
vigorous stirring and the reaction mixture was stirred for 3 h. Benzene (75 mL)
was added to the reaction mixture and insoluble materials were removed by
filtration. The benzene solution was washed with saturated NaCl solution and
dried over sodium sulfate. Then, the solvent is evaporated to get the respective
9-(2-bromobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-1-one (3).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.018.
References and notes
1. Tsuji, J. Palladium Reagents and Catalysts; John Wiley & Sons: New York, 2004. p
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3. Dyker, G. Chem. Ber. 1997, 130, 1567.
4. Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,
1359.
9-(2-bromobenzyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (3a)
Pale yellow solid (0.349 g, 95%); mp: 265 °C; IR (KBr) 3441, 2923, 1657,
1535 cmꢀ1 1H NMR (CDCl3, 400 MHz): d (ppm) 2.23–2.26 (m, 2H, C3–2H), 2.45
;
(s, 3H, CH3), 2.64 (t, 2H, J = 6.0 Hz, 2-2H), 3.05 (t, 2H, J = 6.0 Hz, 4-2H), 5.85 (s,
2H, N–CH2), 6.30 (d d, 1H, J = 6.7 Hz, J = 2.4 Hz, 60-H), 7.03 (d t, 2H, J = 6.7 Hz,
J = 2.4 Hz, 40- & 50-H), 7.08 (d, 1H, J = 8.6 Hz, 8-H), 7.17 (d d, 1H, J = 8.6 Hz,
J = 1.2 Hz, 7-H), 7.47 (d, 1H, J = 1.2 Hz, 5-H), 7.57 (d d, 1H, J = 6.7 Hz, J = 2.4 Hz,
30-H); 13C NMR (CDCl3, 125 MHz) d (ppm) 21.39, 21.92, 24.77, 39.88, 48.34,
110.52, 120.68, 121.86, 125.26, 126.88, 127.60, 128.13, 129.13, 129.48, 130.01,
130.20, 132.57, 137.57, 137.88, 191.81; MS, m/z (%): 370 (M+2, 97), 368 (M+,
100), 352 (15), 273 (26), 183 (12), 113 (10); Anal. Calcd for C20H18BrNO: C,
65.23; H, 4.93; N, 3.80%. Found: C, 65.26; H, 4.97; N, 3.85%.
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23. General procedure for the synthesis of 8H-indolo[3,2,1-de]phenanthridin-10-ol (4):
To a mixture of 9-(2-bromobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-1-one (3,
1 mmol), Bu4NBr (1.5 equiv), and Cs2CO3 (1.5 equiv) in anhydrous DMF (8 mL)
was added Pd(OAc)2 (10 mol %) placed in a pre-heated oil bath at 110 °C for 2 h.
After completion of the reaction, the mixture was cooled and diluted with
water. This was extracted with EtOAc. The combined organic extracts were
washed with aq 1 N HCl, water, brine solution and dried (anhyd Na2SO4). The
solvent was removed by distillation and the crude product was purified by
column chromatography over silica gel using pet. ether as an eluant to give the
final compound 4.
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2-Methyl-8H-indolo[3,2,1-de]phenanthridin-10-ol (4a)
White solid (0.256 g, 90%); mp: 223 °C; IR (KBr) 3428, 2923, 1657, 1537 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d (ppm) 2.70 (s, 3H, CH3), 6.43 (d d, 2H, J = 9.5 Hz,
N–CH2), 7.13 (d, 1H, J = 8.0 Hz, 11-H), 7.40 (t, 1H, J = 8.0 Hz, 12-H), 7.50 (d, 1H,
J = 7.5 Hz, 7-H), 7.71 (t, 1H, J = 7.5 Hz, 6-H), 7.89 (s, 1H, 3-H), 7.92 (t, 1H,
J = 7.5 Hz, 5-H), 8.04 (s, 1H, 1-H), 8.37 (d, 1H, J = 8.0 Hz, 4-H), 8.70 (d, 1H,
J = 8.0 Hz, 13-H), 12.35 (s, 1H, 10-OH); 13C NMR (CDCl3, 125 MHz) d (ppm)
21.98, 48.33, 111.28, 116.55, 117.22, 121.06, 122.06, 122.28, 125.60, 125.99,
126.65, 127.88, 128.36, 129.68, 131.62, 133.56, 133.93, 134.98, 146.72, 160.57;
MS, m/z (%): 285 (M+, 100), 271 (15), 254 (14), 164 (9), 113 (12); Anal. Calcd for
C20H15NO: C, 84.19; H, 5.30; N, 4.91%. Found: C, 84.21; H, 5.33; N, 4.95 %.
24. Shanmugasundaram, K.; Rajendra Prasad, K. J. Heterocycles 1999, 51, 2163.
25. General procedure for the synthesis of 1-(2-bromo-benzyloxy)-9H-carbazole (6):
A
mixture of the respective 1-hydroxycarbazoles (5, 1 mmol), 2-

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E. Yamuna et al. / Tetrahedron Letters 52 (2011) 6030–6034
To mixture of 1-(2-Bromo-benzyloxy)-9H-carbazole (1 mmol), Bu4NBr
bromobenzylbromide (1 mmol) and dried K2CO3 in acetone was refluxed in a
a
steam bath for 3 h. The reaction mixture was monitored by TLC. After
completion of the reaction the excess solvent was removed and dissolved in
ice water and neutralized with ice cold 1:1 HCl. The solid separated was
filtered, washed with water and dried. Then, it was purified by column
chromatography over silica gel using petroleum ether and ethyl acetate (99:1)
to get the respective 1-(2-bromo-benzyloxy)-9H-carbazole (6).
(1.5 equiv) and Cs2CO3 (1.5 equiv) in anhydrous DMF (8 mL) was added
Pd(OAc)2 (10 mol %) placed in a pre-heated oil bath at 110 °C for 2 h. After
completion of the reaction, the mixture was cooled and diluted with water.
This was extracted with EtOAc. The combined organic extracts were washed
with aq 1 N HCl, water, brine solution and dried (anhyd Na2SO4). The solvent
was removed by distillation and the crude product was purified by column
chromatography over silica gel using pet. ether as the eluent to give the final
compound 7.
1-(2-Bromo-benzyloxy)-6-methyl-9H-carbazole (6a):
White solid (0.307 g, 84%); mp: 252 °C; IR (KBr) 3429, 2920, 1675, 1574 cmꢀ1
;
1H NMR (CDCl3, 400 MHz): d (ppm) 2.52 (s, 3H, CH3), 5.33 (s, 2H, O–CH2), 6.93
(d, 1H, J = 8.0 Hz, 60-H), 7.11 (t, 1H, J = 8.0 Hz, 3-H), 7.21 (d t, 1H, J = 8.0 Hz, 40-
H), 7.23 (d, 1H, J = 7.6 Hz, 7-H), 7.32-7.36 (m, 2H, 50& 8-H), 7.58 (d, 1H,
J = 7.6 Hz, 2-H), 7.62 (d d, 1H, J = 8.0 Hz, J = 1.2 Hz, 30-H), 7.67 (d, 1H, J = 7.6 Hz,
4-H), 7.84 (s, 1H, 5-H), 8.20 (bs, 1H, 9-H). 13C NMR (CDCl3, 125 MHz) d (ppm)
21.46, 66.99, 107.40, 110.60, 113.38, 119.50, 120.46, 122.91, 123.83, 124.52,
127.21, 127.63, 128.76, 129.36, 129.55, 130.33, 132.84, 136.27, 137.50, 144.45;
MS, m/z (%): 368 (M+2, 97), 366 (M+, 100), 350 (29), 271 (18), 165 (10), 113 (9);
Anal. Calcd for C20H16BrNO: C, 65.59; H, 4.40; N, 3.82 %. Found: C, 65.55; H,
4.37; N, 3.86%.
10-methyl-2,13-dihydroisochromeno[3,4-a]carbazole (7a):
White solid (0.242 g, 85%); mp: 259 °C; IR (KBr) 3432, 2920, 1623, 1577 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d (ppm) 2.56 (s, 3H, CH3), 5.31 (s, 2H, O–CH2), 7.21
(d, 1H, J = 7.5 Hz, 3-H), 7.29 (d t, 1H, J = 7.5 Hz, J = 1.5 Hz, 4-H), 7.42 (d, 1H,
J = 8.0 Hz, 11-H), 7.43 (d t, 1H, J = 7.5 Hz, J = 1.5 Hz, 5-H), 7.47 (d, 1H, J = 8.0 Hz,
12-H), 7.63 (d, 1H, J = 8.0 Hz, 7-H), 7.77 (d, 1H, J = 8.0 Hz, 6-H), 7.81 (d, 1H,
J = 8.0 Hz, 8-H), 8.09 (s, 1H, 9-H), 8.28 (bs, 1H, 13-H); 13C NMR (CDCl3,
125 MHz) d (ppm) 21.53, 66.71, 106.59, 110.59, 111.93, 113.31, 119.93, 120.48,
122.88, 124.66, 126.31, 127.38, 128.71, 129.12, 129.41, 129.63, 130.19, 136.28,
136.86, 142.68; MS, m/z (%): 285 (M+, 100), 270 (25), 218 (16), 164 (12), 113
(11); Anal. Calcd for C20H15NO: C, 84.19; H, 5.30; N, 4.91 %. Found: C, 84.22; H,
5.35; N, 4.95 %.
26. General procedure for the synthesis of 2,13-dihydroisochromeno[3,4-a]carbazole
(7):