Palladium Catalyzed C?C and C?N Bond Formation via ortho C?H Activation and Decarboxylative Strategy: A Practical Approach towards N-Acylated Indoles

Article abstract of DOI:10.1002/adsc.201700872

A concerted palladium catalyzed C?H activation and decarboxylative strategy has been explored for the efficient synthesis of N-acylated indoles. The process allows a facile step- and atom-economic assembly of 3-arylated indole ring from inexpensive and readily available anilides and cinnamic acids as reacting partners. (Figure presented.).

Full text of DOI:10.1002/adsc.201700872

Title: Palladium Catalyzed C–C and C–N Bond Formation via ortho C–
H Activation and Decarboxylative Strategy: A Practical Approach
towards N–Acylated Indoles
Authors: Saurabh Kumar, Rahul Singh, and Krishna Nand Singh
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700872
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10.1002/adsc.201700872
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium Catalyzed C–C and C–N Bond Formation via ortho
C–H Activation and Decarboxylative Strategy: A Practical
Approach towards N–Acylated Indoles
Saurabh Kumar, Rahul Singh and Krishna Nand Singh*
Department of Chemistry (Centre of Advanced Study), Institute of Science, Banaras Hindu University, Varanasi 221005,
India; E-mail: knsinghbhu@yahoo.co.in; knsingh@bhu.ac.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
co-existing dehydrogenative and decarboxylative
cross coupling.
Abstract.
A
concerted palladium catalyzed C–H
activation and decarboxylative strategy has been explored
for the efficient synthesis of N–acylated indoles. The
process allows a facile step- and atom-economic assembly
of 3-arylated indole ring from inexpensive and readily
available anilides and cinnamic acids as reacting partners.
Carboxylic acids are commercially available in great
structural diversity, easy to store and handle, and can
be readily prepared by means of a large number of
well-established methods, which make them valuable
raw material in organic transformations.[12] Moreover,
the α,β-unsaturated carboxylic acids offer exceptional
regioselectivity unlike the corresponding alkenes or
alkynes, thereby attracting more of the present interest
towards decarboxylative cross coupling. Our group
has recently explored the decarboxylative strategy for
the synthesis of vinyl sulfones, 2-substituted
benzothiazoles, thioamides and α,β-epoxy ketones,
using easily accessible α,β-unsaturated carboxylic
acids as functional surrogate.[13]
Keywords: Synthetic methods; C–H Activation;
Palladium; C–C/C–N bond formation; Decarboxylation
Indoles are the most widely distributed heterocyclic
compounds in nature, and therefore its synthesis and
functionalization has forever attracted a great deal of
attention. Fisher synthesis from phenylhydrazones of
aldehydes and ketones, Gassman synthesis from N–
halo-anilines, Madelung cyclization using N–acyl-o-
toluidines,
Bischler
synthesis
using
α-
arylaminoketones and Batcho-Leimgruber synthesis
involving amino-enamine intermediate are among the
few prominent and extensively used methods to
achieve diverse indole derivatives. N–Acylated
indoles are particularly the cherished targets of
synthetic chemists as they comprise the core nucleus
of many important biologically active molecules and
pharmaceuticals.[1,2] Although there exist several
reports for the synthesis of indoles using ortho
substituted anilides,[3] but those concerning ortho C-H
activation of anilides are still scarce,[4] and the work
by Fagnou, Wen and Saa deserve special attention (cf.
Scheme1).
The C–C and C–N bond formation via C–H
activation/ decarboxylative coupling has gained
considerable current interest owing to its potential as
an appreciated tool for step-economic and
environmentally benign approach in organic
synthesis.[5,6] Various transition metal complexes
involving Ru,[7] Rh,[8] Pd,[9] Ir,[10] and Co,[11] have
been effectively applied for the ortho C–H
functionalization of anilides and other directing
groups. In light of the above, we designed a one pot
strategy for ortho vinylation of anilides using α,β-
unsaturated carboxylic acids as vinyl source adopting
Scheme 1. Synthesis of N-acylated indoles
1
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10.1002/adsc.201700872
Advanced Synthesis & Catalysis
In view of the above and as a part of our ongoing effect of different solvents was then explored. The use
research programme,[14] we wish to report an exigent of TFA and pivalic acid did not assist yielding 3a in
protocol for the palladium catalyzed decarboxylation 54% and 57% respectively (entries 11 & 12), whereas
and chelation assisted synthesis of N–acylated indoles the use of other solvents like DMSO, toluene and n-
(Scheme 1).
butanol along with solvent-free conditions remained
The studies were indeed undertaken with an objective completely futile (entries 13-16). Decreasing the
to achieve the ortho vinylation of anilides by reaction temperature to 120 °C reduced the product
cinnamic acids in the presence of Pd(OAc)2 and yield to 62% (entry 17), while an increase in the
K2S2O8 in AcOH. However, the characterization data reaction temperature could not enhance the yield
did not support the formation of the desired stilbene further. Other palladium catalysts like Pd(TFA)2 and
derivative. Rather to our utmost surprise and pleasure, PdCl2, when examined, could not match the efficacy
we were confronted with a serendipity leading to the of Pd(OAc)2 as they afforded 57% and 42% product
formation of the N–acylated indole 3c (Scheme 2), yields only (entries 18 & 19). An attempt to utilize
whose structure was conclusively proved by the copper catalysts namely Cu(OAc)2 and Cu(OTf)2 also
single crystal X-ray (Figure 1)[15] and was also remained futile (entries 20 & 21). The catalytic use of
corroborated by the spectral data.
Ag2O (0.2 and 0.5 equiv.) could not provide the
product in appreciable amount. Further, the catalytic
combination of Ag2O (20 %) with a co-oxidant
K2S2O8 (1 equiv.) also gave rise to a pretty low yield
(entry 22), thereby compelling the use of equivalent
amount of silver salt. The catalyst concentration was
also varied from 5 to 15 mole % revealing 10 mole %
as the best fit. Thus, the optimum conditions
comprised of Pd(OAc)2 (10 mole %) as catalyst and
Ag2O (1 equiv.) as oxidant in AcOH at 130 °C (entry
7).
Scheme 2.
Table 1. Optimization of reaction conditionsa
Catalyst
(10 mol %) (1 equiv.)
Oxidant
Yiel
db
Entry
Solvent
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
-
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
K2S2O8
NH4S2O8
TBHP
Cu(OAc)2.H2O
AgNO3
Ag2CO3
Ag2O
AgOAc
-
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
CH3COOH 38
CH3COOH 12
CH3COOH
CH3COOH
CH3COOH
0
0
0
Figure 1. ORTEP diagram of 3c.
CH3COOH 70
CH3COOH 72
CH3COOH 57
Encouraged by this unique observation, a model
reaction employing acetanilide (1a) and cinnamic acid
(2a) was then screened thoroughly by varying
different parameters such as catalyst, oxidant, solvent,
temperature and time; and the findings are given in
Table 1. The initial reaction conditions involved the
use of Pd(OAc)2 (10 mol%) and K2S2O8 (1 eq.) in
AcOH (1 ml) at 130 °C for 30 h (entry 1), which gave
rise to the product 1-(3-phenyl-1H-indol-1-
yl)ethanone (3a) in 38% yield. Keeping the use of
Pd(OAc)2 as catalyst, some other oxidants, such as
NH4S2O8, TBHP, Cu(OAc)2.H2O and AgNO3 were
also tried, but they either worked poorly or did not
work at all (entries 2-5). However, when silver salts
like Ag2CO3, Ag2O and AgOAc were used as oxidant,
appreciably high product yields were observed
(entries 6-8). Markedly when the reaction was carried
out in the absence of the oxidant or catalyst, no
9.
CH3COOH
CH3COOH
TFA
0
0
54
57
0
0
0
0
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
PivOH
DMSO
toluene
n-butanol
-
CH3COOH 62c
CH3COOH 57
CH3COOH 42
Ag2O
Ag2O
Ag2O
Ag2O/K2S2O8
Cu(OAc)2
Cu(OTf)2
Pd(OAc)2
CH3COOH
CH3COOH
0
0
CH3COOH 35d
aUsing 1a (2 mmol) & 2a (1 mmol). Isolated yield
after column chromatography, at 120 °C, Ag2O(20
b
c
d
product formation was observed (entries 9 & 10). mol %)/ K2S2O8(1 eq.).
Maintaining other parameters of the entry 7 intact, the
2
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10.1002/adsc.201700872
Advanced Synthesis & Catalysis
With the established conditions in hand, the scope and Ortho substituted 2-chloro cinnamic acid afforded
versatility of the reaction was examined using a somewhat low product yield (3k, 59 %) perhaps due
variety of anilides and cinnamic acids with different to steric factor. The reaction of N-(pyridin-4-
substitution patterns (ortho/meta/para). The outcome yl)acetamide with cinnamic acid and the reaction of
is given in Table 2. Both the reacting partners acetanilide with 3-(thiophen-3-yl) acrylic acid,
containing different electron-donating as well as however failed, (3r and 3s). This may be ascribed to
electron-withdrawing substituent participated nicely the nitrogen or sulfur atoms present in the
in the reaction and offered the desired products 3a-3q heterocyclic moiety, which strongly coordinate with
in reasonably good yields. Anilides containing the metals leading to catalyst poisoning and thereby
electron-rich substituent provided higher yields, while limiting the application of C–H activation.[16] With a
those with electron-deficient substituent gave lower view to explore the applicability of (Z)-cinnamic
conversions. A number of substituent like CH3, Cl, acids in the aforementioned reaction, a representative
OMe and NO2 were well tolerated during the course reaction of cis-2-methoxycinnamic acid with different
of reaction. N-(3-(Trifluoromethyl)phenyl)acetamide anilides
namely
N-phenylacetamide,
N-(p-
also participated in the reaction to afford the product tolyl)acetamide and N-(4-fluorophenyl)acetamide was
3q, albeit in lower yield (41%). Contrarily, cinnamic carried out under the established reaction conditions
acid derivatives with electron-rich substituent gave leading to the formation of the products 3w-3y. It is
lower yields than those with electron withdrawing worthwhile to mention that the reactions using (Z)-
groups.
cinnamic acids also proceeded well with the same
regioselectivity affording 3-substituted indoles. 2-
Substituted indoles were not formed at all in this
reaction due to electronic factors and not due to the
steric factors. The Palladium is probably inserted at
the alpha position of olefin (COOH attached carbon)
which exclusively leads to 3-substituted indoles
exhibiting high regioselectivity.[17]
Table 2. Scope and versatility of the reactiona,b
Based on the existing literature,[18-21] and isolation of
product; a plausible mechanism involving palladium
catalytic cycle is outlined in Figure 2. The reaction is
assumed to proceed via ortho-palladation of the
anilide 1 giving intermediates I and II in succession.
The intermediate II then combines with the α,β-
unsaturated acid 2 to form the intermediates III and
IV sequentially. The intermediate IV finally gives rise
to the product 3 via decarboxylation. The role of
silver salt is presumed to be an oxidant which helps
reoxidize the palladium to its catalytic form and also
assists in the decarboxylation step.[22-24]
aUsing 1a (2 mmol), 2a (1 mmol), Pd(OAc)2 (10
mol%), Ag2O (1 equiv) in closed vessel at 130 °C for
30 h. bIsolated yield after column chromatography.
Figure 2. Plausible reaction mechanism
3
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10.1002/adsc.201700872
Advanced Synthesis & Catalysis
In summary, a practical palladium catalyzed C–H
activation and decarboxylative strategy has been
developed for the synthesis of biologically important
N-acylated indoles from anilides and cinnamic acids.
A reaction pathway involving palladium catalytic
cycle has been proposed.
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Anilide 1 (2 mmol), cinnamic acid 2 (1 mmol), acetic
acid (1mL), Pd(OAc)2 (10 mol %) and Ag2O (1
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5
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10.1002/adsc.201700872
Advanced Synthesis & Catalysis
COMMUNICATION
Palladium Catalyzed C–C and C–N Bond
Formation via ortho C–H Activation and
Decarboxylative Strategy: A Practical Approach
towards N–Acylated Indoles
Adv. Synth. Catal. Year, Volume, Page – Page
Saurabh Kumar, Rahul Singh and Krishna Nand
Singh*
6
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