Palladium-mediated intramolecular O-arylation: A simple route for the synthesis of quino[2,3-c] and quino[3,2-b]carbazoles

Article abstract of DOI:10.1016/j.tet.2010.10.073

A simple route for the synthesis of quinocarbazoles in good yields via palladium-mediated intramolecular arylation involving ortho C-H activation is reported.

Full text of DOI:10.1016/j.tet.2010.10.073

Tetrahedron 66 (2010) 9650e9654
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Palladium-mediated intramolecular O-arylation: a simple route for the synthesis
of quino[2,3-c] and quino[3,2-b]carbazoles
*
Devanga K. Sreenivas, Rajagopal Nagarajan
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 August 2010
Received in revised form 7 October 2010
Accepted 24 October 2010
Available online 29 October 2010
A simple route for the synthesis of quinocarbazoles in good yields via palladium-mediated intra-
molecular arylation involving ortho CeH activation is reported.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
CeH activation
Intramolecular arylation
Quinocarbazoles
ortho Arylation
1. Introduction
When one of the ortho positions has a substituent, only one ring
closure product is formed (75e82%). Various reaction conditions
Arylearyl bond plays an important role in the area of transition
metal mediated reactions.1 Among these cross coupling reactions
are one of the most important tools. Recently, direct arylation of
palladium catalyzed electron rich hetero aromatic rings has begun
to replace the above mentioned methods.2 Intramolecular direct
arylation of arenes using palladium catalysts is one of the very
useful alternative method for the synthesis of various heterocycles,
such as cabazoles, isoquinolines, and indoles.3 Among these car-
bazoles4 and its fused derivatives, such as pyrido,5 pyrrolo,6 and
quinocarbazoles7 have attracted considerable attention from me-
dicinal and synthetic chemists mainly because of the wide range of
biological applications (antitumor,8 anticancer,9 DNA inter-
calator10) displayed by this class of compounds. As a result, im-
mense interest has grown in the development of various methods
for the efficient and rapid synthesis of these molecules. Developing
new synthetic methodologies for the synthesis of biologically active
indole and carbazole skeleton has been our longstanding quest.11
In continuation of our interest, herein we report an efficient and
simple synthetic protocol for the synthesis of quinocarbazoles from
N-alkyl-N-(9-ethyl-H-carbazol-3-yl)-2-iodobenzamides using pal-
ladium-catalyzed intramolecular ortho arylation. In this paper we
described the palladium-catalyzed intramolecular arylation of N-
(9-ethyl-9H-carbazol-3-yl)-2-iodo benzamide derivatives for the
synthesis of two isomers of quinocarbazoles. The formation of two
isomers is due to the presence of two reactive ortho positions.
were varied, such as catalyst, ligands, additives, bases, and solvents
to improve the yield and the regioselectivity of the reaction.
2. Results and discussion
The first attempt of cyclization with N-(9-ethyl-9H-carbazol-
3-yl)-2-iodobenzamide 3 (preparedfrom9-ethyl-3-aminocarbazole
and 2-iodobenzoyl chloride) using various conditions like changing
catalyst, base, and solvent gave unsatisfactory results and starting
material was recovered in most of the cases as shown in Scheme 1.
* Corresponding author. Tel.: þ91 40 66794831; fax: þ91 40 23012460; e-mail
Scheme 1. Attempted synthesis of quinocarbazoles.
address: rnsc@uohyd.ernet.in (R. Nagarajan).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.073

D.K. Sreenivas, R. Nagarajan / Tetrahedron 66 (2010) 9650e9654
9651
Table 1
Biaryl couplinga of N-(9-ethyl-H-carbazole-3-yl)-2-iodobenzamide (3)
Entry
Catalyst
Ligand
Additive
Oxidant
Base
Solvent
Temp (ꢀC)
Time (h)
Yielde (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd/Cb
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
d
PPh3
PPh3
d
TBAB
TBAB
d
Ag2CO3
KOAc
d
DMF
DMSO
140
140
120
150
120
120
120
120
24
24
36
24
12
10
24
24
d
d
d
d
55
70
d
d
d
d
DMF/ACOHc
DMF/DMSOc
DMF
d
TBAB
d
d
K2CO3
KOAc
KOAc
KOAc
KOAc
PPh3
PPh3
PPh3
d
CuI
d
Cu(OAc)2$2H2O
Cu(OAc)2$2H2O
d
DMF/toluened
DMF/toluened
DMF/toluened
d
Pd(OAc)2
d
a
Unless otherwise stated, all reactions were carried out by using 0.1 equiv of catalyst, 0.2 equiv of ligand, 1.5 equiv of additive/oxidant, 2 equiv of base.
Pd/C (0.2 equiv) was used.
Mixture of solvents were used in the ratio 1:1.
(DMF/toluene) used in the ratio 1:1.
Isolated yields. (TBAB¼Tetrabutyl ammonium bromide).
b
c
d
e
When we examined the reaction with oxidants like Cu(OAc)2 and
To avoid homocouple product, we perform the reaction using
N-alkylated amides (Scheme 2). The N-ethyl-N-(9-ethyl-H-carbazol-
3-yl)-2-iodobenzamide 6a successfully underwent cyclization to give
the products 7a and 8a. The two regioisomeric products 7a and 8a are
formed due to the availability of two ortho CeH positions. Then we
made consequential changes to catalyst, ligand, additive, base, and
solvent to improve the yield and regioselectivity. Various reaction
conditions were checked and the details are listed in Table 2.
0
CuI, etc., in a mixture of solvents, homo coupled product N2,N2 -bis
(9-ethyl-9H-carbazol-3-yl)biphenyl-2,20-dicarboxamide
4
was
obtained. Various reaction conditions performed are summarized in
Table 1.
The structure of 4 was also confirmed by the single crystal X-ray
analysis. The ORTEP diagram is shown in Fig. 1.12
We performed the reaction with various catalysts. Among them,
Pd(OAc)2 was found to be the best. Even though Pd/C also gave
better results, yields were poor when substituents were in-
troduced. When PPh3, TBAB were used as ligand and additive, re-
spectively, longer reaction times were required. When we
performed the reaction without ligand and additive, the reaction
proceeded well within 2 h in 88% yield and with good regiose-
lectivity (50:38). All the products were well characterized. The
Table 2
Optimization conditionsa of palladium mediated cyclization of 6a to 7a and 8a
Fig. 1. ORTEP diagram of 4.
Entry Catalyst
Ligand Additive Base
Solvent
Time (h) Yieldg (%)
1
2
3
4
5
6
7
8
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
PdCl2
PPh3 TBAB
PPh3 TBAB
PPh3 TBAB
PPh3 TBAB
PPh3 TBAB
PPh3 TBAB
PPh3
KOAc Toluene
20
24
18
20
10
10
10
10
10
3
24
2
3
3
3
20
45
70
55
80
80
80
80
88
85
nre
88f
80
80
80
20
85
nr
This homo coupling was probably due to the free NeH group of
amide that forms the Pd(II) complexes with both ortho positions,
i.e., C2 and C4 of 3 in the presence of a base to undergo the coupling
reaction.13
Et3N
Et3N
DMSO
DMF
Ag2CO3 DMF
KOAc DMF
K2CO3 DMF
KOAc DMF
KOAc DMF
KOAc DMF
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
K2CO3 DMFþH2Oc
K2CO3 DMFþH2Oc
TBAB
9
10
11
12
13
14
15
16
17
18
d
Pd(OAc)2
Pd/C
d
Pd/Cb
Pd/Cb
K2CO3 DMFþH2Od 24
PdCl2(PPh3)2
Pd(OAc)2
K2CO3 DMF
K2CO3 H2O
3
20
a
Unless otherwise stated, all reactions were carried at 120 ꢀC in a seal tube using
1.5 mL solution, using 0.05 equiv of catalyst, 0.2 equiv of ligand, 1.5 equiv of addi-
tive, 2.5 equiv of base.
b
Pd/C used 10 mol %.
c
DMFþH2O in the ratio 1:0.2 mL.
d
DMFþH2O in the ratio 1:1.
e
No reaction.
f
High regioselectivity and high yield obtained, i.e., (50:38).
Isolated and combined yield of 7aþ8a. (TBAB¼tetrabutylammonium bromide).
g
Scheme 2. Synthesis of quinocarbazole derivatives.

9652
D.K. Sreenivas, R. Nagarajan / Tetrahedron 66 (2010) 9650e9654
Table 3
8.29 ppm. Structure of 7a was further confirmed by the single
crystal X-ray analysis.12 When nitro group is present, the reaction
was proceeded within 2 h with high yield due to its high electron
withdrawing nature. ORTEP diagram of 8b was shown in Fig. 2.14
The ORTEP diagrams of chloro substituted derivatives 7c and 8c
were shown in Fig. 3.14
Synthesis of quinocarbazole derivatives
Entry R1 R2 R3 R4
Amide Yield (%) Cyclized Time (h) Yielda (%)
product
1
2
3
4
5
6
Et
Et
Et
Bn
H
H
H
H
Et
H
6a
79
82
76
75
70
68
7a/8a
7b/8b
7c/8c
7d/8d
7e/8e
7f/8f
2
2
5
3
5
5
50:38
78:12
52:18
60:25
62:16
55:15
Et NO2 6b
Et Cl
Et
6c
6d
6e
6f
The same methodology is also extended to various substituted
1,4-dimethylcarbazoloiodobenzamides 10aeb under optimized
conditions to give the products 11aeb in good yields as shown in
Scheme 3 and Table 4.
H
H
H
Et Cl Et
Et Br Et
a
Isolated yield and regioisomeric ratio of 7aef and 8aef.
effect of the base on the reaction was also investigated. KOAc and
K2CO3 were more effective than the other bases while DMF is better
solvent than DMSO and toluene. No reaction was found to occur at
or below 80 ꢀC.
To examine the versatility of this intramolecular palladium
catalyzed ortho arylation, a number of quinocarbazole annulated
cyclic amide derivatives were synthesized by employing the opti-
mized reaction condition, Pd(OAc)2, K2CO3, and DMF. When the
products 6aef were subjected to cyclization under optimized
conditions, they underwent facile cyclization to give isomeric
products 7aef and 8aef. These results are summarized in Scheme 2
and Table 3.
The two regioisomers were characterized by 1H NMR. In the 1H
NMR spectrum of 7a, two doublets were observed at
8.61 ppm, whereas for 8a two singlets were observed at
d
9.01 and
8.12 and
d
Scheme 3. Synthesis of indolo[2,3-b]phenanthridinone derivatives.
Fig. 2. ORTEP diagram of 7a and 8b.
Fig. 3. ORTEP diagrams of 7c and 8c.

D.K. Sreenivas, R. Nagarajan / Tetrahedron 66 (2010) 9650e9654
9653
Table 4
mode. Anal. Calcd for molecular formula C23H21IN2O: C, 58.99; H,
4.52; N, 5.98%; found: C, 58.89; H, 4.56; N, 5.89%.
Synthesis of indolo[2,3-b]phenanthridinone derivatives
Entry R1 R3 R4
Amide Yield (%) Cyclized Time (h) Yield (%)
product
4.3. General procedure for the preparation of
quinocarbazoles
1
2
Et Et
Et Et
H
10a
79
82
11a
11b
5
4
75
82
NO2 10b
A mixture of compound 6a (0.15 g, 0.3 mmol), anhydrous K2CO3
(0.096 g, 7.5 mmol), and Pd(OAc)2 (0.004 mg, 5 mol %) in DMF was
taken in a seal tube and heated at 120 ꢀC for 2 h with continuous
stirring. After completion of the reaction as monitored by TLC, the
reaction mixture was cooled and water was added (10 mL). A solid
precipitate was formed, extracted with CHCl3 or DCM (3ꢂ20 mL),
and washed with water (3ꢂ20 mL) followed by brine (20 mL) and
dried over Na2SO4. Evaporation of solvent and the crude material
was purified by column chromatography over silica-gel
(100e200 mesh), using EtOAc/hexane (15:85%) as an eluent to give
mixture of the products 7a and 8a. Similarly compounds 7bef,
8bef, and 11aeb were obtained in the same manner.
3. Conclusion
In summary, we have developed a simple and an efficient route
for the synthesis of quinocarbazoles in good yields (70e90%). Our
method is superior to the earlier methods15 in terms of avoiding the
use of toxic, air sensitive phosphine ligands, additives, inert at-
mosphere, and benefits from shorter reaction times. Because of its
generality and simplicity, we believe this method can contribute
further in the area of CeH activation.
4. Experimental
4.3.1. 7,12-Diethyl-7H-indolo[2,3-c]phenanthridin-13
(7a). Yellow solid (0.047 g, 50%); mp 176 ꢀC; IR (KBr): 3051, 2972,
1637, 1483, 1419, 1332, 1302, 1224, 1180, 1072, 798 cmꢁ1 1H NMR
(400 MHz, TMS, CDCl3):
¼9.01 (1H, d, J¼8.0 Hz), 8.61 (1H, d,
(12H)-one
4.1. General procedure
;
d
The procedure does not require inert atmosphere. All the
products obtained were purified by column chromatography using
silica-gel (100e200 mesh). Hexane was used as a co-eluent. 1H and
13C NMR were recorded in Bruker 400 and 100 MHz spectrometer,
respectively. The chemical shifts are reported in parts per million
J¼2.8 Hz), 8.38 (1H, d, J¼4.0 Hz), 7.78 (1H, t, J¼8.0 Hz), 7.66 (1H, d,
J¼8.0 Hz), 7.63 (1H, s), 7.58 (1H, d, J¼8.0 Hz), 7.51 (2H, d, J¼4.0 Hz),
7.19 (1H, m), 4.58 (2H, q, J¼8.0 Hz, NeCH2CH3), 4.49 (2H, q,
J¼8.0 Hz, NeCH2CH3), 1.32e1.50 (6H, m); 13C NMR (100 MHz, TMS,
CDCl3):
d
¼160.8, 141.6, 136.1, 134.0, 132.1, 130.6, 129, 127.5, 126.9,
downfield to TMS (
CDCl3 resonance (
d
¼0) for 1H NMR and relative to the central
125.4, 124.8, 122.3, 121.5, 120.8, 118.9, 118.6, 108.7, 105.7, 101.8, 38,
37.6, 13.8, 12.7; LCeMS: m/z¼341 (MþHþ), positive mode. Anal.
Calcd for molecular formula C23H20N2O: C, 81.15; H, 5.92; N, 8.23%;
found: C, 81.36, H, 5.85; N, 8.32%.
d
¼77.0) for 13C NMR. IR spectra were recorded on
JASCO FT/IR-5300. Elemental analyses were recorded on a Thermo
Finnigan Flash EA 1112 analyzer in School of Chemistry at Univer-
sity of Hyderabad. Mass spectra were recorded on either VG7070H
mass spectrometer using EI technique or Shimadzu-LCMS-2010A
mass spectrometer. Melting points were measured in open capil-
lary tubes and are uncorrected.
4.3.2. 6,12-Diethyl-6,12-dihydro-5H-indolo[2,3-b]phenanth-ridin-
5-one (8a). Yellow solid (0.036 g, 38%); mp 172 ꢀC; IR (KBr): 2974,
2926, 1651, 1440, 1323, 846, 771, 740, 696 cmꢁ1; 1H NMR (400 MHz,
TMS, CDCl3):
d
¼8.64 (1H, d, J¼8.0 Hz), 8.48 (1H, d, J¼7.6 Hz), 8.29
4.2. General procedure for the preparation of
carbazoleiodobenzamide precursors
(1H, s, ArH), 8.22 (1H, d, J¼7.6 Hz), 8.12 (1H, s, ArH), 7.82 (1H, t,
J¼7.2 Hz), 7.63 (1H, d, J¼7.2 Hz), 7.56 (1H, d, J¼7.6 Hz), 7.47 (1H, d,
J¼8.4 Hz), 7.16 (1H, d, J¼7.6 Hz), 4.65 (2H, q, J¼6.8 Hz, NeCH2CH3),
4.49 (2H, q, J¼7.6 Hz, NeCH2CH3), 1.52 (6H, m); 13C NMR (100 MHz,
To the compound 5a (0.5 g, 2.1 mmol) in 10 mL DCM was added
Et3N (0.42 mL, 4.3 mmol), stirred at room temperature for 15 min.
Then the reaction mixture was cooled in an ice bath and added
freshly prepared 2a (0.7 mL, 2.6 mmol) (prepared from o-iodo-
benzoic acid and thionyl chloride) was added drop wise. After
stirring for 15 min the reaction mixture was brought to room
temperature and stirring continued up to 2 h. Water was added to
the reaction mixture and extracted with DCM, washed with brine
(20 mL), and dried over anhydrous Na2SO4. The solvent was evap-
orated and the crude material was purified by column chroma-
tography (25% EtOAc/hexane) to obtain the pure product 6a.
Similarly compounds 6bef and 10aeb were obtained by the same
procedure.
TMS, CDCl3):
d¼160.9, 140.5, 136.8, 133.3, 131.6, 130.5, 128.2, 127.8,
126.7, 126.3, 126.0, 123.4, 122.6, 118.1, 118.0, 116.1, 113.2, 110.4, 109.0,
38.3, 37.6, 13.8, 13.2; LCeMS: m/z¼341 (MþHþ), positive mode.
Anal. Calcd for molecular formula C23H20N2O: C, 81.15; H, 5.92; N,
8.23%; found: C, 81.10, H, 5.98; N, 8.28%.
Acknowledgements
We gratefully acknowledge DST for financial assistance (Project
number: SR/S1/OC-70/2008) and for providing single-crystal X-ray
diffractometer facility in our school. DKS thanks CSIR for Senior
Research Fellowship. DKS also thanks to Rambabu, Kishore and
Bharat for helping in crystal studies.
4.2.1. N-(9-Ethyl-9H-carbazol-3-yl)-2-iodobenzamide (6a). White
solid (0.82 g, 79%); mp 139 ꢀC; IR (KBr): 3047, 2976, 2928, 2866,
Supplementary data
1633, 1485, 1116, 1008, 808, 744 cmꢁ1 1H NMR (400 MHz, TMS,
;
CDCl3):
d
¼8.05 (1H, d, J¼7.6 Hz), 7.9 (1H, s), 7.5 (1H, d, J¼8.0 Hz),
Characterization data, 1H, 13C, LCeMS, and elemental analysis
spectra of all compounds are included in the supplementary data.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.10.073.
7.47 (1H, t, J¼8.0 Hz), 7.36 (1H, d, J¼8.0 Hz), 7.31 (1H, d, J¼8.4 Hz),
7.25 (1H, d, J¼7.6 Hz), 7.19 (1H, d, J¼8.4 Hz), 7.07 (1H, d, J¼6.0 Hz),
6.99 (1H, t, J¼6.0 Hz), 6.69 (1H, t, J¼7.2 Hz), 4.26 (2H, q, J¼7.2 Hz,
NeCH2CH3), 4.09 (2H, q, J¼7.2 Hz, NCH2CH3), 1.47 (3H, t, J¼6.8 Hz,
NeCH2CH3), 1.39 (3H, t, J¼7.2 Hz, NeCH2CH3); 13C NMR (100 MHz,
References and notes
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Harayama, T.; Sato, T.; Hori, A.; Abe, H.; Takeuchi, Y. Synlett 2003, 1141; (c) Liu,
Z.; Larock, R. C. Tetrahedron 2007, 63, 347.
14. The CCDC deposition number of 7a is 772616; molecular formula: C23H20N2O1,
chemical formula weight 340.41, monoclinic, unit cell parameters: a¼9.1260
(18), b¼8.2593 (16), c¼22.851 (5), b¼96.462 (3), space group P21/n. The CCDC
deposition number of 8b is 772619; molecular formula: C23H19N3O3, chemical
formula weight 385.41, monoclinic, unit cell parameters: a¼25.978 (15), b¼11.
634 (2), c¼13.874 (8), b¼121.89 (8), space group C2/c. The CCDC deposition
number of 7c is 772617; molecular formula: C23H19Cl1N2O, chemical formula
weight 374.85, monoclinic, unit cell parameters: a¼5.0196 (7), b¼17.051 (2),
c¼10.5546 (15), b¼90.965 (2), space group P21. The CCDC deposition number of
8c is 772618; molecular formula: C23H19Cl1N2O, chemical formula weight 374.
85, monoclinic, unit cell parameters: a¼5.965 (2), b¼1.4538 (10), c¼13.9605
(13), b¼121.6480 (10), space group C2/c.
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