Synthesis of α-carbolines via Pd-catalyzed amidation and Vilsmeier-Haack reaction of 3-acetyl-2-chloroindoles

Article abstract of DOI:10.1021/ol2000827

A new class of α-carboline derivatives has been synthesized by Pd₂(dba)₃/BINAP catalyzed amidation of 3-acetyl-2-chloroindoles followed by a Vilsmeier-Haack reaction and is reported.

Full text of DOI:10.1021/ol2000827

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1398–1401
Synthesis of r-Carbolines via
Pd-Catalyzed Amidation and
Vilsmeier-Haack Reaction of
3-Acetyl-2-chloroindoles
Arepalli Sateesh Kumar and Rajagopal Nagarajan*
School of Chemistry, University of Hyderabad, Central University (P.O.), Hyderabad-
500 046, India
rnsc@uohyd.ernet.in
Received January 11, 2011
ABSTRACT
A new class of R-carboline derivatives has been synthesized by Pd2(dba)3/BINAP catalyzed amidation of 3-acetyl-2-chloroindoles followed by a
Vilsmeier-Haack reaction and is reported.
Pyrido[2,3-b]indoles (R-carbolines) have been focused due
to their biological activities which are antiviral and
antitumor1 due to the formation of intercalation complexes
with DNA or the inhibition of topoisomerase II.2 R-Carbo-
line derivatives possess anxiolytic or neuroprotectant, anti-
inflammatory activity3 and are inhibitors of IKK-2. The
R-carboline derivatives were also useful for the treatment of
cancer and immune-related diseases.4 The core structure of
the pyrido[2,3-b]indoles is found in several naturally occur-
ring alkaloids and carcinogenic metabolites (Figure 1).5
R-Carbolines were also discerned in cigarette smoke and
pyrolysis of protein-containing food products.6
(1) Helbecque, N.; Berbier, J. L.; Henichard, J. P.; Moquin-Pattey,
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Fram. Zh. 1985, 19, 1054–1056. (b) Peczyska-Czoch, W.; Pognan, F.;
Kaczmarek, L.; Boratynski, J. J. Med. Chem. 1994, 37, 3503–3510.
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1999, 40, 3797–3800. (b) Paolini, L. Sci. Rep. Ist. Super. Sanita 1961, 1, 86. (b)
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Figure 1. R-Carboline and R-carboline containing natural products.
In recent years Pd catalyzed C-N bond formation reac-
tions have been paid great attention because the resulting
molecules have been traditionally valuable in organic synth-
esis and pharmaceuticals7 and have important electronic
(7) Hong, Y.; Senanayake, C. H.; Xiang, T.; Vandenbossche, C. P.;
Tanoury, G. J.; Bakale, R. P.; Wald, S. A. Tetrahedron Lett. 1998, 39,
3121–3124.
r
10.1021/ol2000827
Published on Web 02/11/2011
2011 American Chemical Society

properties.8 These reactions have been extensively studied
by the groups of Buchwald and Hartwig.9 Over the past
decade Pd based catalyst systems using phosphine ligands
have been developed,10 and these systems were very useful in
both industrial and academic laboratories11 on both a
minute and very large scale. While Pd catalyzed amidations
of bromo and iodo compounds were well established,12 and
the amidation of chloro compounds was not. These results
prompted us to explore the Pd catalyzed amidation of
3-acetyl-2-chloroindoles.
Table 1. Optimization of the Pd-Catalyzed Cross-Coupling of
1-(2-Chloro-1-(phenylsulfonyl)-1H-indol-3-yl)ethanone and
Benzamidea
The Vilsmeier-Haack reaction is an efficient and eco-
nomical method fortheformylationofreactivearomatic,13
heteroaromatic,14 and conjugated carbocyclic systems.15
This reaction has great importance in various synthetic
methodologies,16 and the results are noteworthy and ex-
alting. In the literature the synthetic methods for the R-
carbolines involve annulation of the pyridine ring onto
indole derivatives;17 multistep processes having poor yields
and cyclizations of azaindoles18 have been used. Due to the
ubiquity of R-carbolines in many biologically active mole-
cules we are exploring the synthetic methodology for the R-
carboline through the Pd catalyzed cross-coupling amida-
tion reactions of 3-acetyl-2-chloroindoles followed by
cyclization with the Vilsmeier-Haack reaction.
entry
Pd source
Pd(OAc)2
base
solvent
yield(%)b
1
K2CO3
K2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
K2CO3
toluene
toluene
toluene
toluene
dioxane
toluene
toluene
t-BuOH
DMSO
t-BuOH
t-BuOH
t-BuOH
t-BuOH
DME
49
27
41
56
39
43
41
35
20
95
84
76
62
67
45
21
10
40
32
35
2
PdCl2
3
PdCl2(PPh3)2
[(allyl)PdCl]2
Pd(OAc)2/H2O Act
Pd(OAc)2/H2O Act
Pd(OAc)2/H2O Act
Pd(OAe)2/H2O Act
Pd(OAc)2/H2O Act
Pd2((dba)3
Pd2(dba)3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
toluene
DMSO
DMF
Pd2(dba)3
(8) (a) Goodson, F. E.; Hartwig, J. F. Macromolecules 1998, 31,
1700–1703. (b) Kanbara, T.; Oshima, M.; Imayasu, T.; Hasegawa, K.
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34, 3629–3632. (c) Majo, V. J.; Perumal, P. T. J. Org. Chem. 1996, 61,
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Q. Org. Lett. 2007, 9, 2421–2423.
Pd2(dba)3
PdCl2
t-BuOH
t-BuOH
t-BuOH
Pd(OAc)2
PdCl2
a Conditions: 1-(2-chloro-1-(phenylsulfonyl)-1H-indol-3-yl)ethanone
(1.0 mmol), benzamide (1.2 mmol), Pd (1 mol %), BINAP (0.25 mol %),
base (3.0 mmol), solvent (2.0 mL/mmol), 110 °C, 6-24 h. b Isolated yields.
3-Acetyl-2-chloroindoles (1b) can be easily prepared from
the Vilsmeier-Haack reaction of 2-oxindole followed by
protection.19 We initiated probing the conditions under
which the coupling reaction of 1-(2-chloro-1-(phenylsul-
fonyl)-1H-indol-3-yl)ethanone and benzamide proceeded
efficiently. We screened different catalysts and ligands as
depicted in Tables 1 and 2, respectively. We found that the
Pd2(dba)3/BINAP catalyst system is efficient for the cross-
coupling of a variety of primary amides with 3-acetyl-2-
chloroindoles. Significantly better results were obtained by
using this catalyst system as shown in Table 3. For example,
the reaction of 1-(2-chloro-1-(phenylsulfonyl)-1H-indol-3-
yl)ethanone with benzamide using 0.5 mol % of Pd2(dba)3
and 0.25 mol % of (()-BINAP afforded the desired product
(3a) with 95% yield in 6 h as shown in Table 3. The structure
of 3h is also confirmed by the single crystal X-ray crystal
structure as shown in Figure 2.20 Most of the reactions
(16) Marson, C. M. Tetrahedron 1992, 48, 3659–3726.
(17) Liger, F.; Popowycz, F.; Besson, T.; Picot, L.; Galmarini, C. M.;
Joseph, B. Bioorg. Med. Chem. 2007, 15, 5615–5619.
(18) (a) Okuda, S.; Robinson, M. M. J. Am. Chem. Soc. 1959, 81,
740–743. (b) Portela-Cubillo, F.; Surgenor, B. A.; Aitken, R. A.; Wal-
ton, J. C. J. Org. Chem. 2008, 73, 8124–8127. (c) Bonini, C.; Funicello,
M.; Spagnolob, P. Synlett 2006, 1574–1576.
(19) Lu, S. C.; Duan, X. Y.; Shi, Z. J.; Li, B.; Ren, Y. W.; Zhang, W.
Org. Lett. 2009, 11, 3902–3905.
(20) (a) The CCDC deposition number of 3h is 806183; molecular
formula, C14H16N2O2; chemical formula weight is 244.28; triclinic; unit
˚
˚
˚
cell parameters: a 7.1902(14) A, b 10.650(2) A, c 10.795(2) A, R
104.16(3)°, β 103.50(3)°, γ 96.70(3)°, and space group P212121. (b)
The CCDC deposition number of 4a is 806182; molecular formula:
C17H17Cl1N2O1; chemical formula weight is 300.78; triclinic; unit cell
˚
˚
˚
parameters: a 7.1902(14) A, b 10.650(2) A, c 10.795(2) A, R 104.16(3)°, β
103.50(3)°, γ 96.70(3)°, and space group P1.
Org. Lett., Vol. 13, No. 6, 2011
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Table 2. Ligands Effect on Amidation of 1-(2-Chloro-
1-(phenylsulfonyl)-1H-indol-3-yl)ethanonea
ligand
% conversion (time (h))
yield (%)b
PPh3
40 (24)
65 (24)
35 (24)
20 (24)
>4 (24)
53 (24)
32
57
15
-
-
47
PCy3
DPPM
DPPE
DPPP
Figure 2. ORTEP diagram of 3h.
Cyclodiphosphazane-
[ClPN(t-Bu)]2
BINAP
100 (6)
95
Table 4. Vilsmeier-Haack Reaction of Amide Derivatives
a Conditions: 1-(2-chloro-1-(phenylsulfonyl)-1H-indol-3-yl)ethanone (1.0
mmol), benzamide (1.2 mmol), Pd2(dba)3 (0.5 mol %), ligand (0.25 mol %),
Cs2CO3 (3.0mmol),solvent(2.0mL/mmol),110°C, 6-24 h. b Isolated yields.
Table 3. Pd-Catalyzed Cross-Coupling of 3-Acetyl-2-chloroin-
doles and Amides
Having developed a successful method for the synthesis
of N-(3-acetyl-1-(substituted)-1H-indol-2-yl)amides, we
focused on the synthesis of R-carbolines through a Vils-
meier-Haack reaction. The optimal reaction conditions
for the Vilsmeier-Haack reaction were found to involve
the use of 3.0 equiv of POCl3 in DMF at 80-90 °C to give
2-substituted-R-carbolines 4a-h. The conditions proved
to be generally applicable to a wide range of N-(3-acetyl-
1-(substituted)-1H-indol-2-yl)amides 3e-l providing the
appropriate 2-substituted-R-carbolines 4a-h with good
yields as shown in Table 4. The structure of 9-butyl-
4-chloro-2-methyl-9H-pyrido[2,3-b]indol-3-carbaldehyde
4a is also confirmed by single crystal X-ray analysis as
shown in Figure 3.20 This cyclization method is effective
for the synthesis of 9-butyl-4-chloro-9H-pyrido[2,3-b]-
indol-3-carbaldehyde 6a with the use of excess (5 equiv)
proceeded to completion in less than 24 h using the Pd2-
(dba)3/BINAP system. After completion of amidation reac-
tions of 3-acetyl-2-chloroindoles we concluded that an
electron-withdrawing group at the first position of 3-acet-
yl-2-chloroindoles gave excellent yields compared to an
electron-releasing group.
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Org. Lett., Vol. 13, No. 6, 2011

Scheme 1. Possible Mechanism for 4a-h
Figure 3. ORTEP diagram of 4a.
which is formed from the excess of POCl3 and DMF
yielded (g) which is involved in cyclization; elimination
reactions followed by hydrolysis in presence of aqueous
NaOAc gave 6a.
Table 5. Vilsmeier-Haack Reaction of Amide Derivatives
In summary, we described a useful method for the synth-
esis of an array of R-carboline derivatives in good yields
through Pd catalyzed amidation and a Vilsmeier-Haack
reaction. This methodology provided the synthesis of addi-
tional R-carboline derivatives that can be useful for the
various applications involving screening of biological activ-
ities. The biological studies of these R-carboline derivatives is
currently underway in our laboratory.
POCl3 asdepicted in Table 5. 9-Butyl-4-chloro-9H-pyrido-
[2,3-b]indol-3-carbaldehyde (6a) yields are increased when
R1 varies from methyl to thiophenyl.
Acknowledgment. We thank DST for financial support
and for the single-crystal X-ray diffractometer facility in
our school. A.S.K. thanks UGC for a senior research
fellowship. A.S.K. also thanks Rambabu, Kishore, Bhar-
at, Tanmay, Saikat Sen, Srinu, Anand, and Venu Srinivas
for helping in crystal studies.
Possible mechansisms for 4a-h and 6a are depicted in
Schemes 1 and 2 (Supporting Information) respectively. In
Scheme 1, chloromethyleneiminium salt formed from the
DMF and POCl3 reacts with 3e-l and yielded the mono-
chloromethyleneiminium salt (b) which reacts with POCl3
to give (c) which is further involved in electrocyclization
followed by hydrolysis in the presence of aqueous NaOAc
to give 4a-h. In Scheme 2 (Supporting Information),21 (a)
reacts with two molecules of chloromethyleneiminium salt
Supporting Information Available. Experimental pro-
cedures, Scheme 2, spectroscopic data, LC-MS and ele-
mental analysis for all new compounds, and ORTEP
diagram of 4a (disordered butyl side chain). This material
is available free of charge via the Internet at http://pubs.
acs.org.
(21) See the Supporting Information.
Org. Lett., Vol. 13, No. 6, 2011
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