Chemoselective Cu-catalyzed synthesis of diverseN-arylindole carboxamides, β-oxo amides andN-arylindole-3-carbonitriles using diaryliodonium salts

Article abstract of DOI:10.1039/d0ob02247k

Chemoselective copper-catalyzed synthesis of diverseN-arylindole-3-carboxamides, β-oxo amides andN-arylindole-3-carbonitriles from readily accessible indole-3-carbonitriles, α-cyano ketones and diaryliodonium salts has been developed. DiverseN-arylindole-3-carboxamides and β-oxo amides were successfully achieved in high yields under copper-catalyzed neutral reaction conditions, and the addition of an organic base (DIPEA) resulted in a completely different selectivity pattern to produceN-arylindole-3-carbonitriles. Moreover, the importance of the developed methodology was realized by the synthesis of indoloquinolones andN-((1H-indol-3-yl)methyl)aniline and by a single-step gram-scale synthesis of the naturally occurring cephalandole A analogue.

Full text of DOI:10.1039/d0ob02247k

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Chemoselective Cu-catalyzed synthesis of diverse
N-arylindole carboxamides, β-oxo amides and
N-arylindole-3-carbonitriles using diaryliodonium
salts†
Cite this: Org. Biomol. Chem., 2021,
19, 1109
Manish Kumar Mehra, Monika Malik, Bintu Kumar and Dalip Kumar
*
Chemoselective copper-catalyzed synthesis of diverse N-arylindole-3-carboxamides, β-oxo amides and
N-arylindole-3-carbonitriles from readily accessible indole-3-carbonitriles, α-cyano ketones and diarylio-
donium salts has been developed. Diverse N-arylindole-3-carboxamides and β-oxo amides were suc-
cessfully achieved in high yields under copper-catalyzed neutral reaction conditions, and the addition of
an organic base (DIPEA) resulted in a completely different selectivity pattern to produce N-arylindole-3-
carbonitriles. Moreover, the importance of the developed methodology was realized by the synthesis of
indoloquinolones and N-((1H-indol-3-yl)methyl)aniline and by a single-step gram-scale synthesis of the
naturally occurring cephalandole A analogue.
Received 11th November 2020,
Accepted 30th December 2020
DOI: 10.1039/d0ob02247k
rsc.li/obc
ditions.7 In recent years, diaryliodonium salts have been
widely employed as highly electrophilic and relatively benign
Introduction
N-Arylamide and related compounds are ubiquitous units arylating coupling partners under mild reaction conditions.8
present in numerous medicinally potent molecules and In relation to this, the reaction of diaryliodonium salts with
organic materials.1 Particularly, arylamides are recognized for arylnitriles has been utilized to access diversely substituted
their various medicinal properties such as anti-inflammatory, nitrogen-heterocycles such as quinazolines, quinolines,
anti-tumour, and potassium channel activation.2 Therefore, phenanthridines, isoindolines and benzoxazines.9 These
the synthesis of N-arylamide has attracted greater interest from copper-catalyzed reactions of arylnitriles with diaryliodonium
organic and medicinal chemists. One of the most widely used salts proceeded through N-aryl nitrilium intermediates.
synthesis methods to obtain N-arylamides is the Goldberg Furthermore, cascade annulation of this intermediate with
reaction, involving the coupling of aryl(alkyl)amides and aryl nitriles or acetylenes provided quinazoline and quinoline
halides in the presence of a copper catalyst and a base at high derivatives at high temperatures. While developing an efficient
temperature.3 However, this method typically suffers from the method for the synthesis of quinazoline and quinoline deriva-
need for harsh reaction conditions, a narrow substrate scope tives, the Chen group detected N-arylamide as a side product10
and low product yields. In recent years, the Goldberg reaction and rationalized its formation by preparing N-phenyl pentana-
has been advanced by employing ligands with copper catalysts mide and N-phenyl-1-naphthamide. However, Chen’s research
in non-polar solvents.4 In this regard, the alkyl- or arylamide work mainly focused on the synthesis of various nitrogen-het-
reactants used in the Goldberg reaction could be prepared erocycles. Therefore, we envisioned that the use of easily acces-
easily from their corresponding nitriles by hydrolysis.5 In 2013, sible (NH)-indole-carbonitriles or α-cyano ketones as substrates
Pan and colleagues described a copper-catalyzed synthesis of instead of amides and diaryliodonium salts as arylating agents
benzanilides in water by the reaction of haloarenes or alkenyl could be an alternative convenient approach to obtain N-aryl-
halides with arylnitriles using ionic liquid as a phase transfer amides. Particularly, we aimed to capably synthesize bioactive
catalyst.6 Similarly, in 2016, Yang and co-workers developed a N-arylindole-carboxamides and β-oxo amides from the reaction
protocol for amidation involving the reaction of arylboronic of readily accessible free (NH)-indole-carbonitriles or α-cyano
acids with various arylnitriles under copper-catalyzed con- ketones with diaryliodonium salts under milder conditions.
Furthermore, multisite-selective C–N bond formation is criti-
cally important due to its applications in the structural modifi-
Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031,
cations of medicinally potent and privileged scaffolds.
Rajasthan, India. E-mail: dalipk@pilani.bits-pilani.ac.in
However, chemoselective C–N bond formation for the intro-
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
duction of aryl groups remains a distinct challenge because of
d0ob02247k
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the problems associated with controlling the arylation at reaction of different anilines and indole-3-carboxylic acids 8
precise positions. using 2-chloro-1-methyl-pyridinium iodide (Mukaiyama
On the other hand, indole amides are a class of very impor- reagent) and tributylamine in toluene at 90 °C.21 Using the
tant heterocyclic compounds which are widely present in reaction of indole-3-carboxylic acids 8 with arylamines in the
many natural products and pharmacological agents. In this presence of EDCI·HCl (1-ethyl-3-(3-dimethyl-aminopropyl)
context, the development of a new synthetic route to access a carbodiimide hydrochloride) and HOBt (hydroxybenzo-tri-
variety of indole-carboxamides is still desirable because the azole), Nakano et al. prepared indole amide derivatives 5
existing methods often suffer from low product yields and (Scheme 1).22
narrow substrate scope.11 In addition, indole carboxamides
have found many applications as pharmacophores. As depicted
in Fig. 1, APICA (1) is identified as a cannabinoid receptor
agonist, JNJ-7777120 (2) acts as a selective antagonist at the
Results and discussion
histamine H4 receptor, and phenylglycine-01 (PG-01) (3) is Although syntheses of N-arylindole-3-carboxamides have been
known as a cystic fibrosis transmembrane conductance regula- disclosed in the literature, the substrate scope is limited.19–24
tor (CFTR) potentiator.12 Cephalandole B (4) is a naturally Furthermore, there is no report available to access
occurring alkaloid which was isolated from the cytotoxic N-arylindole-3-carboxamides from indole-3-carbonitriles and
methanol extract of the Taiwanese orchid Cephalanceropsis gra- diaryliodonium salts. The broad substrate scope and easy
cilis (Orchidaceae).12e
Among the amides, β-oxo amides represent a valuable struc- the reaction of indole-3-carbonitriles and the relatively benign
tural unit in medicinal and synthetic organic chemistry.13 diaryliodonium salts to achieve
library of bioactive
Recently, extensive research efforts have been directed towards N-arylindole-3-carboxamides24 under mild reaction conditions.
the synthesis of β-oxo amides because they are potential pre- Indole-3-carbonitriles 9 can be easily accessed in two syn-
preparation of indole-3-carbonitriles prompted us to explore
a
cursors to achieve a variety of bioactive heterocyclic com- thetic steps from their corresponding substituted indoles. The
pounds,14 i.e., pyridones,15 quinolones,16 and chromones.17 Vilsmeier–Haack reaction of indole produced 3-formylindole
But, most of the existing methods to prepare β-oxo amides which upon treatment with hydroxylamine and sodium
suffer from disadvantages such as the formation of undesir- formate in formic acid afforded the corresponding indole-3-
able side products in stoichiometric amounts, the need for carbonitriles 9 (refer to the ESI†).
high reaction temperatures, and a narrow substrate scope.18
Initially, we chose indole-3-carbonitrile (9a) and diphenylio-
In 2015, the Kassiou group prepared indole-3-carboxamides donium triflate (10a) as model substrates to investigate the
5 by the reaction of N-protected indole-3-carbonyl chlorides 6 reaction conditions (Table 1). The reaction of 9a with 10a
and their corresponding amine derivatives using triethylamine using CuCl (10 mol%) as the catalyst and 1,2-dichloroethane
(TEA) in DCM (Scheme 1).19 Veale et al. performed the syn- (DCE) as solvent at 80 °C under a N2 atmosphere resulted in
thesis of 5 by refluxing indole-3-carbonyl cyanides 7 and the expected N-phenylindole-3-carboxamide (11a) in 20% yield
amine derivatives (3.0 equiv.) in acetonitrile.20 Likewise, Xu (Table 1, entry 1). The use of CuI instead of CuCl as the catalyst
and co-workers prepared N-arylindole-3-carboxamides 5 by the decreased the yield of 11a (Table 1, entry 2). Gratifyingly, chan-
ging the catalyst from CuI to Cu(OTf)2 produced 11a in 91%
yield (Table 1, entry 3). The use of Cu(OAc)2H2O instead of Cu
(OTf)2 afforded 11a only in trace amounts (Table 1, entry 4).
Noticeably, the reaction failed to provide the expected product
11a in the absence of the catalyst or when iodobenzene was
used as a coupling partner (Table 1, entry 5). This control
experiment revealed the essential role of the copper catalyst
and high reactivity of diphenyliodonium triflate (10a). Next, we
focused on optimizing the catalyst loading. No significant
Fig. 1 Potent pharmacophores with indole carboxamide linkages 1–4.
improvement in the yield of 11a was observed when the
amount of Cu(OTf)2 was increased from 10 mol% to 20 mol%
(Table 1, entry 6). Notably, a lower product yield (11a, 80%)
was observed when the catalyst loading was reduced (5 mol%)
(Table 1, entry 7). Furthermore, variation in the reaction temp-
eratures also did not improve the yield of 11a significantly
(Table 1, entries 8 and 9). The reaction yield also decreased in
the absence of a N2 atmosphere (Table 1, entry 10) and no
product was detected under strictly anhydrous conditions
(Table 1, entry 11). The use of solvents such as toluene, DMF,
and THF resulted in lower product yields (Table 1, entries
Scheme 1 General synthetic routes for indole carboxamides 5.
1110 | Org. Biomol. Chem., 2021, 19, 1109–1114
12–14). Next, the reactivity of diphenyliodonium salts with
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Table 1 Optimization of reaction conditionsa,b
Table 2 Synthesis of N-arylindole-carboxamidesa,b
Counterion
(X)
Catalyst
(10 mol%)
Temp.
(°C)
Yieldb
(%)
Entry
Solvent
1.
2.
3.
4.
5.
6.
7.
8.
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTs
Br
CuCl
CuI
Cu(OTf)2
Cu(OAc)2H2O
—
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Dry DCE
Toluene
DMF
THF
DCE
DCE
DCE
80
80
80
80
80
80
80
100
60
100
80
80
80
80
80
80
80
20
10
91
Trace
NRc,d
92e
80 f
90
9.
75
10.
11.
12.
13.
14.
15.
16.
17.
40g
NR
79
10
78
55
45
PF6
85
a Reaction conditions: 9a (0.70 mmol, 1.0 equiv.), 10a (0.84 mmol, 1.2
equiv.), catalyst (0.07 mmol, 0.1 equiv.), DCE (2.5 mL) under a N2
atmosphere at 80 °C for 12 h. b Isolated yield of the product. c NR = no
reaction. d Iodobenzene was used instead of 10a. e 20 mol% catalyst
was used. f 5 mol% catalyst was used. g Reaction was performed in the
absence of a N2 atmosphere.
OTs, Br and PF6 counterions (Table 1, entries 15–17) was inves-
tigated. The reaction of 9a with diphenyliodonium salt 10a
having OTs and Br counterions afforded 11a in poor yields
(55% and 45%, respectively), whereas the reaction of 10a with
PF6 counterions provided 11a in 85% yield. The relatively
a Reaction conditions: 9a–f (0.70 mmol, 1.0 equiv.), 10 (0.84 mmol, 1.2
equiv.), Cu(OTf)2 (0.07 mmol, 0.1 equiv.), DCE (2.5 mL) under a N2
atmosphere at 80 °C for 12 h. b Isolated yield of the product.
better coordinating and nucleophilic nature of OTs and Br complex structures through various cross coupling reactions.
counterions in diphenyliodonium salts could be responsible The strong electron-withdrawing nitro group (9e) at the C5
for the poor product yields when compared to 10a bearing OTf position of indole-3-carbonitrile showed credible reactivity to
and PF6 counterions.25
give the product 11i in 78% yield. Furthermore, when the
With the optimized conditions in hand, the generality of N-methyl protected substrate (9e) was subjected to reaction
the protocol was then examined with indole-3-carbonitrile (9a) with 10a, delightfully, the reaction worked well to provide 11j
and various diaryliodonium salts (10a–h). The reaction of 9a in 85% yield (Table 2b). It is noteworthy that indole 9f with a
with diaryliodonium salts having electron-donating substitu- cyano group at the C2 position reacted smoothly under the
ents such as methyl (10b), t-butyl (10c) and methoxy (10d) at optimized reaction conditions to produce 11k in 81% yield.
the para-position proceeded smoothly to afford the corres-
Next, we moved our attention to explore the amidation of
ponding products 11b (89%), 11c (80%) and 11d (82%) structurally different α-cyano ketones (12a–d, Table 3) under
(Table 2a). Compound 9a with an electron-withdrawing group the optimized reaction conditions. In this ambiance, the reac-
also reacted effectively with (4-chlorophenyl)(mesityl)iodonium tion of α-cyano ketone (12a) with diphenyliodonium triflate
triflate (10e) to furnish 11e in 75% yield. Interestingly, meta- (10a) under standard conditions successfully afforded the
substituted mesityl(m-tolyl)iodonium triflate (10f) afforded the corresponding β-oxo amide 13a in 75% yield (as shown in
product 11f in excellent yield (86%). Furthermore, we explored Table 3). Under the developed reaction conditions, the electron
the viable substrate scope by employing diversely substituted donating group (methoxy, 12b) and the halo substituted
indole-3-carbonitriles (Table 2b). Indole-3-carbonitriles with (bromo, 12c) α-cyano ketone underwent facile amidation to
halogen substituents such as Br (9b) and F (9d) worked well, afford the desired N-phenyl-β-oxo amides 13b and 13c, respect-
and the corresponding products 11g and 11h were obtained in ively, in good yields (64–70%). Furthermore, 3-oxo-3-phenyl-
good yields of 75% and 70%, respectively. The tolerance of the propane-nitrile (12d) also reacted well to produce 13d in 82%
halogen group can provide great potential to prepare more yield.
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Table 3 Synthesis of various β-oxo amides (13a–d) a,b
9a with diaryliodonium salts having electron rich methyl (10b)
and electron deficient ester (10g) groups.
To demonstrate the synthetic usefulness of the amidation
methodology, we targeted the gram-scale synthesis of the natu-
rally occurring alkaloid, cephalandole A analogue, isolated
from the Taiwanese orchid Cephalanceopsis gracilis.28
Fortunately, under standard conditions, the reaction of 9a
(1.0 g, 7.04 mmol) with 10h directly gave the cyclic product 15
(63%) in a single step as shown in Scheme 2A. Furthermore,
the released iodomesitylene was also recovered in 60% yield
after the reaction and it was reused to prepare mesityl(p-tolyl)
iodonium triflate (10b). Next, we successfully reduced 11a to
achieve the useful precursor (for spirooxindoles) N-((1H-indol-
3-yl)methyl)aniline (16) in 42% yield (Scheme 2B).29 As
depicted in Scheme 2C, the prepared indole carboxamides 11j
and 11k were effectively utilized to prepare the corresponding
indoloquinolones 17 (72%) and 18 (65%) in good yields.
Indoloquinolones have great pharmaceutical value as they are
present in several biologically active molecules30 and are key
precursors for the synthesis of various indoloquinoline alka-
loids such as cryptosanguinolentine and isoneocryptolepine.31
Based on our results and previous literature reports,7,9a,10-
a Reaction conditions: 12a–d (0.70 mmol, 1.0 equiv.), 10a (0.84 mmol,
1.2 equiv.), Cu(OTf)2 (0.07 mmol, 0.1 equiv.), DCE (2.5 mL) under a N2
atmosphere at 80 °C for 12 h. b Isolated yield.
N-Arylation of various heterocycles utilizing diaryliodonium
salts as the coupling partner has been reported under copper-
catalyzed basic reaction conditions.26 Interestingly, the
addition of 3.0 equiv. of an organic base (DIPEA) under the
developed copper-catalyzed amidation conditions led to the
tuning of the selectivity pattern and resulted in N-arylindole-3-
carbonitriles, which may be useful to access various dibenzaze-
pine, pyrrolo[3,2,1-jk]carbazole and indoloquinoline deriva-
tives.27 The chemoselective reaction of indole-3-carbonitrile
(9a) with 10a using 10 mol% Cu(OTf)2 and DIPEA (3.0 equiv.)
in dichloroethane at 80 °C under an inert atmosphere provided
1-phenylindole-3-carbonitrile (14a) in 93% yield (as depicted
in Table 4).
a,32
a plausible reaction mechanism for this transformation is
illustrated in Scheme 3. Initially, disproportionation or
reduction of Cu(OTf)2 by the substrate molecule may generate
the active catalyst Cu(I)OTf. Next, oxidative addition of diarylio-
donium triflate 10 may convert Cu(I)OTf A to copper(III) inter-
To test the feasibility of the reaction, the present strategy
was suitably utilized to prepare two more 1-arylindole-3-carbo-
nitrile derivatives 14b (85%) and 14c (79%) by the reaction of
Table 4 Chemoselective synthesis of N-arylindole-3-carbonitrilesa,b
a Reaction conditions: 9a (0.70 mmol, 1.0 equiv.), 10 (0.84 mmol, 1.2
equiv.), Cu(OTf)2 (0.07 mmol, 0.1 equiv.), DIPEA (2.1 mmol, 3.0
equiv.), DCE (2.5 mL) under a N2 atmosphere at 80 °C for 12 h.
b Isolated yield.
Scheme 2 Synthetic applications to access various heterocycles.
Reaction conditions: (i) Methyliodide (3.0 equiv.), NaH (2.0 equiv.), THF,
0 °C to reflux, 4 h. (ii) 10 mol% Pd(OAc)2, 20 mol% t-BuOK, AgOAc (3.0
equiv.), PivOH : AcOH (3 : 1), 130 °C for 12 h.
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Acknowledgements
The authors are highly grateful to CSIR, New Delhi, for
research grant [Ref. No. 02(0290)/17/EMR-II] and Senior
Research Fellowship (MKM). The authors are also thankful to
DST, New Delhi and BITS Pilani for HRMS (DST-FIST) and
NMR facilities.
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Conclusions
In summary, we have developed a copper-catalyzed general strat-
egy for chemoselective C–N bond formation to prepare
N-arylindole-carboxamides, β-oxo amides and N-arylindole-3-
carbonitriles using readily available indole-carbonitriles,
α-cyano ketones and relatively benign diaryliodonium salts
under mild reaction conditions. The addition of an organic
base plays an important role in tuning the chemoselectivity of
the two reactive sites. Diaryliodonium salts with different substi-
tuents including the electron-donating and electron-withdraw-
ing groups could smoothly deliver the desired products in good
to excellent yields (up to 93%). Furthermore, structurally
different and readily available α-cyano ketones also afforded the
corresponding arylated β-oxo amides in high yields (64–82%)
under the developed amidation conditions. Moreover, the appli-
cability of the developed protocol was proved by the single-step
gram-scale synthesis of the naturally occurring cephalandole A
analogue. The preparation of N-((1H-indol-3-yl)methyl)aniline
and potent heterocyclic scaffold indoloquinolones showed the
further synthetic usefulness of indole carboxamides. Also, the
prepared indole carboxamides and arylated β-oxo amides could
be useful precursors to access other heterocycles.
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Conflicts of interest
There are no conflicts to declare.
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