PdBr2-catalyzed direct synthesis of 2,3-disubstituted indoles via a tandem reaction between arylamines and α-diketones

Article abstract of DOI:10.1016/j.tetlet.2011.10.025

A direct PdBr₂(BINAP)-complex catalyzed method has been developed to produce 2,3-disubstituted indoles by the reaction of arylamines with α-diketones under reductive (H₂) conditions. The synthetic methodology involves a tandem reaction of three steps and all the organic intermediates were isolated and characterized, the reduction products in this sequence are chiral and present interesting enantiomeric excess. This report constitutes a new and different route to synthesize indoles and a plausible mechanism is also suggested.

Full text of DOI:10.1016/j.tetlet.2011.10.025

Tetrahedron Letters 52 (2011) 6758–6762
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[(S)-BINAP]PdBr2-catalyzed direct synthesis of 2,3-disubstituted indoles
via a tandem reaction between arylamines and a-diketones
⇑
A. Cabrera , P. Sharma, M. Ayala, L. Rubio-Perez, Manuel Amézquita-Valencia
Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Circuito Exterior, Coyoacán 04510, México D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct PdBr2(BINAP)-complex catalyzed method has been developed to produce 2,3-disubstituted
Received 21 June 2011
Revised 4 October 2011
Accepted 6 October 2011
Available online 15 October 2011
indoles by the reaction of arylamines with
a-diketones under reductive (H2) conditions. The synthetic
methodology involves a tandem reaction of three steps and all the organic intermediates were isolated
and characterized, the reduction products in this sequence are chiral and present interesting enantio-
meric excess. This report constitutes a new and different route to synthesize indoles and a plausible
mechanism is also suggested.
Keywords:
2,3-Alkylindoles
Ó 2011 Elsevier Ltd. All rights reserved.
a-Diketones
Arylamines
Palladium catalysis
Chiral ligands
Introduction
have been reported, the development of new methods for the syn-
thesis of indoles remains an active area of research, here we report
Substituted indoles are common and important heterocyclic
compounds found in nature,1 the indole moiety is present in a range
of pharmaceutical agents and materials. Substituted indoles partic-
ipate in different biological functions including as building blocks
for proteins. Among the several types of substituted indoles, C(2)–
C(3) substituted indoles are of special interest because these com-
pounds are important promising therapeutic agents2 and display
antiestrogen antagonist, antiinflammatory, and cytotoxic proper-
ties. Various synthetic methods are reported in the literature for
substituted indoles,3–5 in the past years palladium-catalyzed syn-
theses ofsubstitutedindoles usingC–C and C–X bond formingroutes
are reported.5b Annulation of 2-iodo-anilines and disubstituted al-
kynes a pioneering work of Larock,6 cyclization of b-(2-iodophenyl)
unsaturated ketones or esters a report by Sakamoto,7 Heck cycliza-
tion of bromoenaminones reported by Chen et al.,8 the intramolecu-
lar Heck cyclization of aryl iodides reported by Tietse9 are some of
the reports that can be cited in this context. Recently hetero
annulation of 2-haloaniline and phenyl acetylene to produce
2-substituted indole derivatives reported by Oskooie et al.,2 and a
recent communication of Cacchi et al. on palladium-catalyzed syn-
thesis of 2,3-disubstituted indoles from arenediazonium tetra-
fluoroborates and 2-alkynyltrifluoro acetanilides10 are some other
reports that also mention the palladium-catalyzed syntheses of
these heterocycles. Although a number of routes for indole synthesis
for the first time a new tandem catalytic way to synthesize indoles.
Results and discussion
In continuation to our research on the synthesis of chiral aro-
matic amines by direct asymmetric reductive amination of carbonyl
compounds,11 using air stable preformed chiral palladium–phos-
phine complexes, a new direct method has been found for the
synthesis of 2,3-disubstituted indoles by the heteroannulation of
a-diketones and aromatic amines, via a homogeneous C–H activa-
tion of aromatic amines, in the presence of hydrogen pressure
(Scheme 1). The C–H activation is one of the most interesting
research fields in palladium-catalyzed annulation.12,13
A very good yield of indole derivatives was obtained when
symmetric substrates were used, but when non-symmetric a-dike-
tones were used (Table 1, entries 2 and 3), only one of the two pos-
sible products is obtained and the more substituted C-2 product is
NH2
R
2
O
R1
+
[(S)-BINAP]PdBr2
R1
R2
H2 800 Psi
CH2Cl2, 120°C, 24h
N
O
H
⇑
Corresponding author.
E-mail address: arcaor1@servidor.unam.mx (A. Cabrera).
Scheme 1. Formation of 2,3-disubstituted indoles via reductive amination of
diketones with aniline.
a-
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.025

A. Cabrera et al. / Tetrahedron Letters 52 (2011) 6758–6762
6759
preferred. This preference suggests that the final annulation step is
highly sterically dependent and in consequence, the cyclization
proceeds via the nucleophilic addition to less sterically hindered
carbonyl group.
When p-anisidine was reacted with a symmetric a-diketone viz.
benzil (PhCOCOPh) an expected indole (Table 1, entry 7) was
product of imine was observed, probably because the involvement
of non-bonding electrons on p-methoxy group, gives an electron-
delocalization extended until the second phenyl group. This will af-
fect the C@N bond which becomes more conjugated, consequently
a retardatory effect on hydrogenation rate of this imine must be
observed. Compound (12a) was formed as an intermediate in the
reaction and was isolated and characterized (Fig. 1).
obtained along with imine (12a). But in this reaction no reduction
Table 1
Synthesis of 2,3-disubstituted indole from
a
-diketones and aromatic amines
Entrya
a
-Diketone
Amine
Product
Yieldb (%)
O
1c
100
1
N
H
O
NH2
a
1a
2a
O
2c
2c
3c
98
2
N
H
O
NH2
a
O
Traces
2
O
N
H
NH2
a
2a'
3a
O
95
3
N
H
O
NH2
a
O
3c
Traces
3
O
NH2
a
N
H
3a'
4a
O
4d
100
100
4
O
O
N
H
NH2
a
O
5c
N
H
NH2
5a
6a
a
5
O
6d
99
NH2
a
O
6
N
H
(continued on next page)

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A. Cabrera et al. / Tetrahedron Letters 52 (2011) 6758–6762
Table 1 (continued)
Entrya
a
-Diketone
Amine
OMe
Product
Yieldb (%)
O
7d
40
MeO
O
6
NH2
b
N
H
7b
a
Reaction conditions: a-diketone(1 mmol), amine (1 mmol), H2 (800 psi), [(S)-BINAP]PdBr2 (0.025 mmol), temp 120 °C, CH2Cl2 (10 mL).
Determined by GC–MS analysis.
24 h.
48 h.
b
c
d
When the reaction time was lowered from 48 to 24 h for sub-
strate 6 (entry 11, Table 2) a chiral amine intermediate 11a was
isolated and characterized. This procedure was extended to other
substrates, and an interesting chiral induction in these reaction
products was observed (Table 2), this suggests the additional pos-
sibility to synthesize chiral indolines via an additional hydrogena-
tion step,15 with this catalytic system.
Based on these results, we report a novel direct synthesis of 2,
3-disubstituted indoles which involves three steps viz. mono amina-
tion of
a-diketone giving an imine intermediate followed by a
catalytic reduction giving chiral amine and final annulation-dehy-
dration reaction to obtain the indole. It is shown schematically in
Scheme 2.
One proposed pathway to account for these palladium-cata-
lyzed reaction is offered in Scheme 3, although details await fur-
ther investigations. Reductive amination of
a-diketone gives
aminoketone I in equilibria with its tautomeric form II which is
activated by the metallic species forming a palladacyclic complex
as suggested in Pd-catalyzed cyclization of oxime acetates13 fol-
lowed of reductive elimination to give the indole derivative.
Figure 1. Thermal ellipsoid plot of imine 12a (40% probability).14
Table 2
Formation of a-amino ketones intermediates in the synthesis of 2,3-disubstituted indoles
Entrya
a-Diketone
Amine
Intermediate
Time (h)
Yieldb (%)
eec (%)
O
O
8
12
70
73
N
2
H
O
NH2
a
8a
O
O
9
a
a
12
12
73
90
96
N
H
9a
3
O
O
O
10
1
4
O
N
H
10a

A. Cabrera et al. / Tetrahedron Letters 52 (2011) 6758–6762
6761
Table 2 (continued)
Entrya
a-Diketone
Amine
Intermediate
Time (h)
Yieldb (%)
eec (%)
O
O
11
a
24
79
82
O
6
N
H
11a
a
Reaction condition:
Isolated yield.
Determined by HPLC analysis with Daicel chiracel OD-H column.
a-diketone(1 mmol), amine (1 mmol), H2 (800 psi), [(S)-BINAP]PdBr2 (0.025 mmol), temp 120 °C, CH2Cl2 (10 mL).
b
c
R
O
NH2
N
NH
R
Reduction
Annulation
Dehydratation
+
Ammination
Dehydratation
R
R
N
H
O
O
O
Scheme 2. Direct three step formation of 2,3-disubstituted indole via reductive amination annulation process.
L2
Pd
R2
R1
N
H
H2O
Ph
R
HN
R
PdL2Br2
PdL2(OH)
R
H2
R
OH
R
R
2HBr
Ph NH
II
I
N
H
PdL2
R
O
R
H2
Ph
NH
Ph
N
O
R
L2(H)Pd
R
Pd(H)(H)L2
NH2
H2O
O
R
N
O
R
R
R
Ph
O
Scheme 3. Suggested pathway for indole synthesis.

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A. Cabrera et al. / Tetrahedron Letters 52 (2011) 6758–6762
Conclusion
References and notes
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disubstituted indoles from -diketones, in very good yields is
a
reported. Further studies on the effect of substituent groups on
the nucleophilic amines and the confirmation of the mechanism
proposed for this process are in progress.
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Acknowledgments
We thank DGAPA–UNAM for the financial support (PAPIIT
IN203209), SNI (340/5840) and CONACyT (Fellowship 229448).
We also thank A. Toscano, S. Hernández-Ortega, J. Pérez, L. Velasco,
L. C. Marquez and E. Garcia for the technical support.
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14. Supplementary Material Crystallographic data for the structural analysis have
been deposited with the Cambridge Crystallographic Data Centre CCDC No.
830787.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.025.
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