Rhodium(iii)-catalysed aerobic synthesis of highly functionalized indoles from N-arylurea under mild conditions through C-H activation

Article abstract of DOI:10.1039/c4cc06020b

A Rh(iii) catalysed amino arylation of alkynes using copper as the terminal oxidant for regeneration of the catalytically active species under aerobic conditions is described. This novel C-H activation reaction was applied to the synthesis of a wide range of substituted indoles from N-arylureas.

Full text of DOI:10.1039/c4cc06020b

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Rhodium(III)-catalysed aerobic synthesis of highly
functionalized indoles from N-arylurea under mild
conditions through C-H activation
Cite this: DOI: 10.1039/x0xx00000x
Subban Kathiravan,a and Ian A. Nichollsa,b*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
presented a rhodium (III) catalysed oxidative coupling of N-acetyl
anilines and alkynes through a chelation assisted metalation pathway
with high regioselectivity.[8] Glorius developed a hydrazine directed
traceless redox neutral N-N bond cleavage strategy involving
oxidizing directing groups coupling with alkynes,[9] while Huang
developed triazene directing groups for alkyne annulation to access
unprotected indoles, in which the N=N bond of the triazene is
cleaved in the reaction.[10] Recently the use of hydrazones, azines,
and N-oxides in combination with additives for C-H activation has
been reported.[11]
A Rh(III) catalysed amino arylation of alkynes using copper
as the terminal oxidant for regeneration of the catalytically
active species under aerobic conditions is described. This
novel C-H activation reaction was applied to the synthesis of
a wide range of substituted indoles from
N-arylureas.
Nitrogen-containing heterocycles are ubiquitous in both natural
products and pharmaceuticals, therefore the development of new
selective and user friendly methods for their preparation is of
importance.[1] The indole moiety is one of the more common
nitrogen containing structural motifs present in drugs, natural
products, and other functional molecules.[2] The Fischer indole
synthesis has remained one of the most widely accepted techniques
among the synthetic community due to its operational simplicity and
general functional group tolerance. However, the development of
alternative synthesis strategies starting from less expensive and more
readily available reagents is of interest, e.g. the Larock procedure
which makes use of modified aniline derivatives, such as ortho-
haloanilines, in the presence of palladium catalysts.[3] More recently,
Glorius and co-workers developed a divergent method based upon a
palladium-catalysed oxidative cyclization of aniline and ketone
derived N-aryl enamines to afford the corresponding indoles,[4] and
Yoshikai has explored the use of palladium catalysed aerobic
oxidative cyclization of N-arylimines for improving substrate
scope.[5] In another example, Ackermann demonstrated that indole
synthesis could take place via a selective copper catalyzed amination
of dihaloarenes followed by a palladium catalysed C-H activation
reaction.[6]
We envisaged that the development of an operationally simple
catalytic system, where copper is used as the terminal oxidant in air,
would simplify the practical use of Rh-catalysed C-H activation
reactions. Herein, we report a mild protocol for the Rh(III) catalysed
aminoarylation of internal alkynes with N-arylurea that uses readily
available catalysts. We propose that this development is based upon
the combination of a urea auxiliary for promoting C-H activation and
copper as oxidant for closing the catalytic cycle under aerobic
conditions.
Table 1. Optimization studiesa
Scheme 1.
Generally, Rh(III) catalysed C-H activation directed by heteroatom
containing groups has rapidly emerged as a fruitful field for
developing a diverse range of catalytic carbon-carbon and carbon-
heteroatom bond forming reactions.[7] A number of initial attempts to
use rhodium catalysed chelation assisted metalation approaches for
indole synthesis have been described. Fagnou and co-workers have
aAll reactions were carried out under the following conditions: 1a (1.5 mmol), 2a (1
mmol), [RhCp*Cl2]2 (1 mol%), additive (20 mol%) and Cu(OAc).H2O (1.0 equiv.), in
b
solvent (2 mL) at 1000C for 12 h under air; R=Me, Yields were determined by
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integration of 1H NMR spectra, by using mesitylene as an internal standard. Rh(III) =
[Cp*RhCl2]2, Ru(II) = [(p-Cymene)RuCl2]2, Ir(III) = [IrCp*Cl2]2, (NR=No reaction).
arylurea 1a and found that the corresponding sterically crowded
polyphenyl substituted indoles (4g&4h) in reasonable yields (79%
and 65%). That the coupling of a heterocyclic thiophene motif could
be performed in excellent yield was pleasing. When asymmetrical
alkynes 2j, and 2k-2m were employed a 1:0 regioselectivity was
observed.
Our study was initiated using the 4-methoxy phenyl substituted N-
aryl urea 1a and diphenylacetylene 2a in the presence of
[Cp*RhCl2]2 as catalyst precursor. The C-H activation reaction of 1a
and 2a was tested with a series of solvents, such as tert-amylOH, 2-
methyl-1-butanol, tert-BuOH, THF, DMF, DMSO, dichloromethane,
1,2-dichloroethane (1,2-DCE), 1,4-dioxane, toluene, methanol,
ethanol, AcOH, and CF3COOH. Among them, 1,2-DCE was
effective, providing 3a in 70 % yield. Next, various additives (20
mol%; AgBF4, KPF6, AgOTf, AgCO3, AgNO3 and AgSbF6) in the
presence of Rh(III) catalyst in 1,2-DCE as solvent at 1000C for 12 h
under air was screened (Table 1, entries 1-5). While, AgBF4 was not
effective for the reaction (entry 1), KPF6 and AgOTf demonstrated
some affectivity, yielding 3a in 38 and 45% yield, respectively
(entries 2 and 3). AgCO3 and AgNO3 were also completely not
effective (entries 4 and 5). AgSbF6 was found to be very effective
Table 2. Scope of N-arylureaa,b
for this reaction affording the product 3a in 85
% NMR
spectroscopic yield (entry 6). Next, the indole synthesis was
examined with various oxidants, including K2S2O8, Na2S2O8,
(NH4)2S2O8, Ag2O, AgOAc, PhI(OAc), and Cu(OAc)2.2H2O. Of
these, only Cu(OAc)2.H2O was demonstrated to be very effective,
affording the product 3a in 92 % yield (entry 7).
The reaction was then tested with two alternative catalysts [(p-
[12]
cymene)RuCl2]2
and [IrCp*Cl2]2. Although the Ru(II) catalyst
demonstrated some efficiency, furnishing 3a in 55 % yield (entry 7),
the Ir(III) catalyst was totally ineffective (entry 8). Based on these
optimization studies, we have concluded that AgSbF6,
Cu(OAc)2.2H2O, and 1,2-DCE in the presence of [RhCp*Cl2]2 at
1000C for 12 h under air offers the best conditions for this C-H
activation reaction.
aAll reactions were carried out under the following conditions: 1a (1.5 mmol), 2a (1
mmol), [RhCp*Cl2]2 (1 mol%), additive (20 mol%) and Cu(OAc).H2O (1.0 equiv.), in
solvent (2 mL) at 1000C for 12 h under air. b Yields were determined by integration of
1H NMR spectra, by using mesitylene as an internal standard., (NR= no reaction).
Table 3. Scope of alkynes a,b
With the optimized reaction conditions in hand, the scope of this
reaction was examined with various ortho, para, and meta-
substituted N-arylureas, 1a-1r, with diphenylacetylene 2a (Table 2).
The C-H activation reaction is compatible with electron donating,
halogen, and electron-withdrawing functional groups such as Me, H,
I, Br, Cl, and F substituted N-aryl urea 1a-1r. Thus, 4-methoxy 1a
and unsubstituted 1b N-arylurea reacted with 2a gave indole 3a and
3b in 92 and 80% yield respectively. Substrates containing a methyl
group at the ortho position, 1c, halogen groups such as F (1d), Cl
(1e), and Br (1f) substituted arylureas were effectively involved in
the reaction, providing indole derivatives 3c-3f in 68, 55, 78 and
60% yields, respectively. Ureas bearing electron donating groups
such as methoxy 1g, 3,4-dimethoxy 1h, and 4-ethyl 1i afforded the
corresponding products 3g-3i in 80, 75, 95% yield respectively. In
the case of electron deficient ureas, e.g. ester 1j, nitro 1k, and cyano
1l, were also screened under optimized reaction conditions. While
the ester substituted urea afforded 3j in 85%, the more strongly
electron withdrawing nitro and cyano (3k and 3l) substituents did
not yield corresponding products. Next, the indole synthesis was
tested with the para- 1m, meta- 1n, and m,p- 1o methyl substituted
ureas provided the corresponding indoles 3m-3o in moderate yields
(62, 71 and 63%). The sterically hindered ortho-F 1p, and ortho-Br
1q, substituted ureas offered the corresponding indole 3p-3q in trace
quantities.
aAll reactions were carried out under the following conditions: 1a (1.5 mmol), 2a (1
mmol), [RhCp*Cl2]2 (1 mol%), additive (20 mol%) and Cu(OAc).H2O (1.0 equiv.), in
b
solvent (2 mL) at 1000C for 12 h under air; Yields were determined by integration of
1H NMR spectra, by using mesitylene as an internal standard.
To further explore the scope of this method the reaction was tested
with urea derivatives such as N-(4-methoxyphenyl)-1-
pyrrolidinecarboxamide 5a, which under similar reaction conditions
provided the corresponding indole 6a in very good yield (91%)
(Scheme 3).
We then turned our attention to the substituent on the alkyne (Table
3). When the aromatic group was replaced with an alkyl chain the
reactivity of the substrate was greatly enhanced, and gave 2,3-ethyl,
propyl, and butyl substituted indoles (4a-4c) in 92%, 85%, and 88%
respectively. This reaction was not restricted to aromatic
substituents, as para substituted methyl, methoxy and chloro
diphenylacetylene derivatives (2d & 2f) could also be used in this
protocol, although moderate yields were obtained. Next, this reaction
was extended with 1, and 2-bromonaphthalenes (2g&2h) with N-
Scheme 3.
2 | J. Name., 2012, 00, 1-3
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bDepartment of Chemistry, BMC, Uppsala University, SE-751 23
Uppsala, Sweden
To gain insights into the mechanism for the intermolecular C-H
aminoarylation of alkynes with N-arylureas, we performed a kinetic
isotopic exchange study using the pentadeuterated substrate 1b-[D5]
(Scheme 4). The observed H/D scrambling indicated that the C-H
activation step is reversible in nature.
†
Electronic Supplementary Information (ESI) available: [Experimental
procedures, full spectroscopic data for all new compounds]. See
DOI: 10.1039/c000000x/
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Scheme 6. Removal of directing group
Conclusions
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In summary, we have developed a mild and efficient operationally
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arylureas with alkynes to prepare N-carbamoyl indoles under aerobic
reaction conditions. Conveniently, this reaction can be carried out
under aerobic conditions, and efficient removal of the N-carbamoyl
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reaction also demonstrates broad substrate scope, providing access to
a wide range of indoles, and even highly sterically crowded indole
derivatives. The demonstration of the use of air enabled C-H
activation provides guidance for further development of mild and
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This research was supported by the generous financial support
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Notes and references
a
Bioorganic & Biophysical Chemistry Laboratory, Linnaeus University
Centre for Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar,
Sweden, Fax: (+) 46 0480-446244, E-mail: ian.nicholls@lnu.se
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Graphical Abstract
Rhodium(III)-catalysed
aerobic
synthesis of highly functionalized
indoles from N-arylurea under mild
conditions through C-H activation
Subban Kathiravan,a and Ian A. Nichollsa,b*
4 | J. Name., 2012, 00, 1-3
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