Palladium(II) in electrophilic activation of aldehydes and enones: Efficient C-3 functionalization of indoles

Article abstract of DOI:10.1016/j.tetlet.2015.08.080

The regioselective C-3 alkylation of indoles with aldehydes and enones as electrophiles is catalyzed by a d⁸ late transition metal complex PdCl₂(MeCN)₂ at room temperature in the presence of air/moisture and in the absence

Full text of DOI:10.1016/j.tetlet.2015.08.080

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
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Palladium(II) in electrophilic activation of aldehydes and enones:
efficient C-3 functionalization of indoles
Swapna Sarita Mohapatra a, Priyabrata Mukhi a, Anuradha Mohanty a, Satyanarayan Pal b,
Aditya Omprakash Sahoo c, Debjit Das c, Sujit Roy a,
⇑
a Organometallics & Catalysis Laboratory, School of Basic Sciences, Indian Institute of Technology, Bhubaneswar 751013, India
b Department of Chemistry, Ravenshaw University, Cuttack 753003, India
c Centre for Applied Chemistry, Central University of Jharkhand, Brambe, Ranchi 835205, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselective C-3 alkylation of indoles with aldehydes and enones as electrophiles is catalyzed by a
d
in the absence of any additional acid/base, additive, or ligand. The active catalyst in this alkylation is an
organometallic intermediate C1 which is formed from the reaction of indole with the palladium(II)
pre-catalyst. The crystallographic characterization and reactivity of C1 and its analogs with indoles and
surrogates is in progress.
8 late transition metal complex PdCl2(MeCN)2 at room temperature in the presence of air/moisture and
Received 11 June 2015
Revised 26 August 2015
Accepted 27 August 2015
Available online xxxx
Keywords:
Alkylation
Palladium
Indole
Ó 2015 Published by Elsevier Ltd.
Carbonyl
Catalysis
C–C bond formation
Alkylated indoles are important structural motifs frequently
found in natural products, pharmaceuticals, and other functional
synthetics.1 Bisindolylmethane (hereafter BIM) derivatives show
promising biological activities such as anti-pyretic, anti-fungal,
anti-inflammatory, anti-convulsant, cardiovascular, selective
b-glucuronidase and COX-2 inhibitory activities.2,3 In addition,
the oxidized forms of BIMs are utilized as dyes as well as colori-
metric chemosensors.2 Hence, the development of highly selective
and efficient strategies for the synthesis of these moieties has cap-
tured wide attention. A number of protic and Lewis acids are
reported for the synthesis of BIMs from indole and carbonyl com-
pounds.2,4 Other catalysts ranging from dinuclear zirconium(IV)
complex, and phenalenyl (PLY) cation to one dimensional CdS
nanorods have found place in recent literature.5 It may be noted
that the pursuit to develop new catalysts for BIMs arises from
issues such as (a) minimizing the catalyst loading, (b) enhancing
the turnover frequency, and (c) easing the work-up protocol. We
believe that a strategy which addresses the above issues for the
synthesis of BIMs will be highly attractive.
allylation and benzylation of indoles with respective alcohols.7
Aided by this insight and excited by the opportunity that BIMs
provide, we present here an efficient and regioselective C-3
functionalization of indoles with aldehydes and enones using
PdCl2(MeCN)2 as the catalyst. It is well known that the said Pd(II)
catalyst is either readily available or can be prepared in the labora-
tory very easily. More importantly the title reaction neither
requires the assistance of external acid/base, additive, and ligand,
nor is it sensitive toward moisture and air. The work-up procedure
is also easy.
In model studies, we examined the reaction of indole 1a with
benzaldehyde 2a at room temperature for 10 h leading to the
formation of bis(indolyl)methane 3a as the desired product; the
solvents and catalysts (5 mol % loading) being varied (Table 1). In
case of palladium(II) catalysts, simple salts as well as complexes
were included. While the conversion was very low with palla-
dium(II) acetate (entry 2), with palladium(II)chloride the conver-
sion (70%) and isolated yield of 3a (65%) were moderate (entry
3). Among the complexes screened, only PdCl2(MeCN)2 showed
promising catalytic activity in 1,2-dichloroethane (DCE) as the sol-
vent, with >95% conversion; the isolated yield of 3a being 80%
(entry 6). When the reaction was conducted in toluene, the conver-
sion (70%) and isolated yield of 3a (62%) were moderate (entry 7).
In contrast, very poor conversion was observed in coordinating
solvents like acetonitrile and methanol (entries 8 and 9). It may
In parallel to our major research program on multimetallic
catalysis,6 recently we noted that Pd(II) efficiently catalyzes the
⇑
Corresponding author.
E-mail address: sujitroy.chem@gmail.com (S. Roy).
http://dx.doi.org/10.1016/j.tetlet.2015.08.080
0040-4039/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Mohapatra, S. S.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.08.080

2
S. S. Mohapatra et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 1
be noted that, while initial studies were conducted using Schlenk
Catalyst screeninga
technique, soon it was found that the reactions could be conducted
in simple glass vials and in the presence of air and moisture. Under
similar conditions, we also checked a few known catalysts, which
resulted in isolated yields ranging from 50–70% (entries 10–13).
The scope and limitation of the BIM-forming reaction were
evaluated under the optimized conditions (Table 1, entry 6) using
O
H
Catalyst (5 mol%)
Solvent, rt,10h
N
H
N
H
N
H
1a
3a
2a
various substituted aldehydes
2 and ring substituted (but
N-unsubstituted) or N-substituted (alkyl, benzyl, allyl, and propar-
gyl)indoles 1 (Table 2). Gratifyingly, in most cases the correspond-
ing BIM derivatives 3 were obtained in moderate to good yields
(Table 2, entries 1–19). Notably, in all cases where we have used
N-unsubstituted indoles, the reactions were completely C-3 selec-
tive and no N-alkyl products were formed (entries 1–9). Aromatic
aldehydes, with electron-withdrawing groups at o- and p-posi-
tions, provided products in good yields and at shorter reaction time
(entries 14–16, 18 and 19). On the other hand, reaction of aldehy-
des with electron donating groups took a longer time for full con-
version and the isolated yields of desired products were moderate
(entries 7, 10, and 12). This could probably be due to the decrease
in electrophilicity at the aldehydic carbon atom.8 Gratifyingly,
under the present reaction conditions, heterocyclic aldehydes like
2b or 2f survived well without the formation of any side products
and the corresponding bis(indolyl)methanes 3b or 3f were isolated
in good yield. However aliphatic aldehydes 2c and 2d (entries 3
and 4) showed lower reactivity compared to their aromatic coun-
terparts; while aromatic ketones (entries 20 and 21) were totally
#
Catalyst
Solvent
Conversionb (%)
Yield of 3ac (%)
1d
2
3
4
5
6
7
8
9
10
11
12
13
Nil
Pd(OAc)2
PdCl2
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
MeOH
CH3CN
DCE
<10
<10
ꢀ70
<5
—
—
65
—
—
80
62
—
PdCl2(PPh3)2
PdCl2(bpy)e
<5
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
Cu(NO3)2ꢁ3H2O
SnCl2ꢁ2H2O
Sc(OTf)3
>95
ꢀ70
<10
<10
ꢀ80
ꢀ55
ꢀ80
ꢀ75
—
70
50
70
62
DCE
DCE
DCE
InBr3
a
Unless otherwise mentioned, reaction condition: aldehyde (0.25 mmol), indole
(0.5 mmol), catalyst (5 mol %) in 2 mL of DCE at 30 °C for 10 h.
From 1H NMR.
b
c
Isolated yield of chromatographically pure product.
Reaction time 4d.
bpy = 2,20-bipyridine.
d
e
Table 2
PdCl2(MeCN)2 catalyzed synthesis of bis(indolyl)methanes: substrate scopea
R2
R2
R3
R4
R2
O
R4
R3
PdCl2(MeCN)2 (5 mol%)
DCE, rt
N
R1
N
N
R1
R1
1
2
3
#
1
Indole
Carbonyl compound
Time (h)
10
Yield of 3 (%)
3a, 80
N
H
2a
1a
CHO
OHC
O
2b
2
3
4
10
16
15
3b, 82
3c, 61
3d, 50
N
H
1a
1a
CHO
N
H
2c
(CH2)7CHO
H3
C
2d
N
1a
H
MeO
5
6
7
3e, 96
3f, 80
N
H
1b
CHO
2e
MeO
Br
OHC
S
2f
10
N
H
1b
CH3
N
H
7
24
3g, 48
1c
2g
CHO
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S. S. Mohapatra et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
Table 2 (continued)
#
Indole
Carbonyl compound
Time (h)
24
Yield of 3 (%)
3h, 85
Br
NO2
N
H
8
1c
2h
CHO
Br
Cl
N
H
9
10
24
24
10
3i, 60
3j, 81
3k, 75
3l, 80
1c
2i
CHO
CH3
N
Me
10
11
12
1d
1d
2g
CHO
Cl
N
Me
2i
CHO
OCH3
N
N
2j
Ph
1e
CHO
13
14
10
4
3m, 86
3n, 88
CHO
2e
CHO
Cl
Ph
1e
1e
N
2k
Ph
NO2
N
N
N
15
16
8
6
3o, 90
3p, 74
2h
2l
1f
CHO
CN
1f
1f
CHO
CH3
17
18
3
2
4
3q, 97
3r, 75
3s, 95
2g
CHO
CHO
N
N
Cl
2k
1f
CN
19
20
1g
2l
CHO
O
10
10
NRb
NRb
N
H
2m
1a
O
Ph
21
N
1a
H
2n
a
All reactions for the preparation of BIM’s were carried out with aldehyde (0.25 mmol), indole (0.5 mmol), and PdCl2(MeCN)2 (5 mol %) in 2 mL of DCE at room temperature
30 °C.
b
NR: no reaction.
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S. S. Mohapatra et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Cl
Cl
Pd
DCE, rt
MeCN
+
PdCl2(MeCN)2
2
N
H
N
H
Complex C1
Scheme 2. Formation of complex C1.
Table 4
Complex C1 catalyzed synthesis of bis(indolyl)methanes: substrate scopea
R2
R2
R3
R2
O
H
C1;
Complex
DCE, rt
R1 = H; R2 = H, Br;
R3
N
R3= 4-H, 4-CH3, 4-Cl
R1
N
N
R1
R1
1
2
3
#
Indole
Complex C1
(mol %)
Aldehyde
Time (h)
Yield of 3 (%)
Figure 1. ORTEP diagram of 3q with 30% probability thermal ellipsoid (CCDC No.
1405691).
1
2
5
3
10
10
3a, 83
3a, 80
N
H
2a
1a
CHO
N
H
2a
1a
O
R'
O
H
CHO
PdCl2(MeCN)2 (5 mol%)
DCE, rt, 10h
Br
CH3
+
+
NH
N
H
3
4
5
5
24
10
3g, 50
3i, 61
HN
NH
1c
1c
3a
2g
R' = Me, Ph
CHO
Cl
Scheme 1. Aldehyde selective C-3 alkylation.
Br
N
H
2i
CHO
a
Table 3
All reactions for the preparation of BIM’s were carried out with aldehyde
PdCl2(MeCN)2 catalyzed C-3 functionalization of indoles with enonesa
(0.25 mmol), indole (0.5 mmol), and complex C1 in 2 mL of DCE at room temper-
ature 30 °C.
R2
R2
PdCl2(MeCN)2 (5 mol%)
O
R4
O
R4
R5
R5
DCE, rt
unreactive. It may be noted that, the crystal structure of 3q showed
that the two N-allyl groups are furthest away from each other in
the molecule (Fig. 1).
N
N
R1
1
4
R1
5
The sharp difference in the reactivity between an aldehyde and
a ketone in the title reaction, prompted us to investigate the
chemoselectivity of the reaction. Reaction of a 1:1:2 mixture of
benzaldehyde, acetophenone (or benzophenone), and indole for
10 h afforded exclusively the corresponding benzaldehyde derived
bis(indolyl)methane 3a (Scheme 1). These results show the high
chemoselectivity toward the aldehyde in the present method.
With the success as above we next explored the scope of the
present palladium catalyzed C-3 alkylation of indole with elec-
trophiles other than aldehydes. In our hand electrophiles such as
enones were also effective at room temperature (Table 3). Michael
addition of indoles with enones 4a–4c furnished corresponding
products 5a–5e in moderate to good yield (entries 1–5). On the
other hand chalcone 4d was inactive (entry 6).
During the course of experimentation, we noticed that the color
of the solution turns to ochre-red after the addition of
PdCl2(MeCN)2 to a solution of only indole or to a mixture contain-
ing indole and the electrophile (aldehyde or enone) in DCE or DCM.
Previously we have shown that, due to the labile nature of acetoni-
trile ligand, the reaction of PdCl2(MeCN)2 and indole leads to the
formation of an ochre-red colored complex C1 (Scheme 2).7 The
complex C1 was characterized in detail and the probable structure
was enumerated.9
#
1
Indole
Enone
Time (h)
6
Yield of 5 (%)
5a, 72
O
O
4a
N
Et
1h
2
3
6
6
5b, 70
5c, 80
4a
N
H
1a
Br
O
O
4b
4b
N
H
1c
4
5
6
2
5d, 89
5e, 70
NRb
N
H
1a
1a
1a
Ph
6
O
N
H
4c
Ph
Ph
12
O
N
H
4d
a
All Michael addition reactions were carried out with enone (0.6 mmol), indole
(0.5 mmol), and PdCl2(MeCN)2 (5 mol %) in 2 mL of DCE at room temperature 30 °C.
b
NR: no reaction.
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S. S. Mohapatra et al. / Tetrahedron Letters xxx (2015) xxx–xxx
5
To test whether complex C1 is indeed the active catalyst in the
References and notes
present alkylation reaction, we briefly tested its efficiency in the
reaction of indoles with aromatic aldehydes (Table 4).10 We are
delighted to find that, the yields of BIMs obtained with complex
C1 as catalyst are comparable to those of PdCl2(MeCN)2 (entries
1, 3 and 4). Interestingly, the reaction of 1a with 2a is promoted
by complex C1 even at 3% loading (entry 2 vs entry 1).
From the above results, it is therefore evident that PdCl2(MeCN)2
is a pre-catalyst in the present alkylation reaction. Once in solution,
an active catalyst (akin to complex C1) is formed from the corre-
sponding indole and PdCl2(MeCN)2. These results also explain the
inactivity or less reactivity of other Pd(II) complexes with strong
donor ligands (like PPh3, bipy or acetate) (Table 1, entries 2, 4, and 5).
In conclusion we would like to apprise the reader about the
highlights and immense scope of the present work. The present
work demonstrates the ability of a Pd(II) catalyst, belonging to a d8
late transition element, for the electrophilic activation of carbonyl,
leading to C–C bond formation in a Friedel–Crafts like alkylation
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d8-element.11 From the mechanistic point of view, our demonstration
that complex C1 is an active catalyst is very exciting. Note that, in our
view, complex C1 is an organometallic species. Efforts are going on
in our laboratory to grow crystals of this active catalyst and their
analogs with other indoles and surrogates. Once we succeed in enu-
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Acknowledgements
11. The activation of enone may possibly be governed by such interaction. Efforts
are underway to isolate active species from the reaction of complex C1 with
enone to look into the above hypothesis.
Financial support from DST – India (to S.R.), DST-Inspire
Program (fellowship to S.S.M.), UGC – India (fellowship to A.M.)
and Institute (fellowship to P.M.) is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.08.
080.
Please cite this article in press as: Mohapatra, S. S.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.08.080