A copper-mediated oxidative coupling route to 3H- and 1H-indoles from N-aryl-enamines

Article abstract of DOI:10.1002/ejoc.201500112

A facile copper(II)-mediated C-H bond oxidation and C-C bond formation procedure has been applied to the synthesis of indole derivatives. Intramolecular oxidative coupling of 3,3-disubstituted enamines proceeded using a non-expensive and air-stable copper

Full text of DOI:10.1002/ejoc.201500112

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500112
A Copper-Mediated Oxidative Coupling Route to 3H- and 1H-Indoles
from N-Aryl-enamines
Pauline Drouhin[a] and Richard J. K. Taylor*[a]
Keywords: Heterocycles / 1H-Indole / 3H-Indole / Copper-mediated coupling / Cyclization
A facile copper(II)-mediated C–H bond oxidation and C–C
bond formation procedure has been applied to the synthesis
of indole derivatives. Intramolecular oxidative coupling of
ford the corresponding C-3 quaternary indolenine products
in good to excellent yields. 1H-Indoles can be prepared in a
similar manner but in this case, Cu(OAc)2·H2O has been
3,3-disubstituted enamines proceeded using a non-expens- found to be the preferred oxidant.
ive and air-stable copper salt, Cu(2-ethylhexanoate)2, to af-
most often by the dearomatisation of indoles.[3] Recently, a
Introduction
number of approaches have been developed for the synthe-
sis of 3H-indole derivatives relying on more challenging in-
tramolecular cyclisation processes.[4] Of particular relevance
to this work, Li and co-workers recently reported an iodine-
mediated synthesis of 3H-indoles by the intramolecular
cyclisation of enamines.[5]
Following our continued interest in the development of
new approaches for the formation of biologically relevant
heterocycles[6] (first started in 2009 with the discovery of
the CuII-mediated cyclisation to oxindoles; Scheme 1), we
have expanded the scope of such cyclisation processes to
various indole-containing heterocycles. Herein, we report
that N-aryl-enamines are excellent substrates for the synthe-
sis of C-3 quaternary indolenines and 3-substituted indoles
by CuII-mediated oxidative coupling.
Indole derivatives are commonly found in a range of bio-
logically active natural (1,[1a] 2,[1b] 3,[1b] and 4;[1c] Figure 1)
and unnatural compounds such as the antibacterial agent
5.[1d] Among the family of indoles, 3,3-disubstituted ind-
olenine (3H-indole) skeletons have attracted considerable
attention, possibly explained by their challenging ind-
olenine ring and the presence of a quaternary C-3 atom.
Moreover, 3H-indoles have been employed as precursors for
the synthesis of indoline natural products, such as physov-
enine (4; Figure 1).[2]
Figure 1. Examples of C-3 quaternary indolenines and indoline
compounds.
Scheme 1. Copper-mediated cyclisation approach to 3H- and 1H-
indoles.
Therefore, the development of synthetic methods for this
privileged structure has been explored by many researchers,
[a] Department of Chemistry, University of York
Heslington, York, YO10 5DD, United Kingdom
E-mail: richard.taylor@york.ac.uk
Results and Discussion
http://www.york.ac.uk/chemistry/staff/academic/t-z/rtaylor/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500112.
Initial experiments, summarised in Table 1, were carried
out using the readily available enamine[5] 8a prepared from
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P. Drouhin, R. J. K. Taylor
SHORT COMMUNICATION
the corresponding aniline and β-dicarbonyl compound. The fully characterised. Also, we were able to obtain a suitable
cyclisation was then investigated, initially using Cu(OAc)2· crystal of the indolenine product 9h for X-ray crystallo-
H2O in mesitylene at 170 °C, conditions optimised for our graphic analysis and conclusively confirmed its structure
preliminary results on the formation of oxindoles.[6d] How- (Figure 2).
1
ever, only 21% yield (estimated by H NMR analysis after
purification) of cyclised product 9a was formed (Entry 1).
The low yield of the reaction appeared to be the result of
addition of water to the reactive enamine functionality giv-
ing 11. To overcome this issue, we switched the source of
copper to commercially available Cu(2-ethylhexanoate)2
and fitted the reaction condenser with a CaCl2 drying trap,
but still under air. Pleasingly, the cyclisation of 8a occurred
in an improved 78% yield (Entry 2). However, reduction of
the amount of copper in the reaction significantly reduced
the yield of the cyclisation (Entry 3). It is also worth noting
that this protocol does require the presence of copper. Heat-
ing of the enamine precursor in mesitylene at 170 °C re-
sulted only in the decomposition of 8a (Entry 4). Based on
literature precedent,[5,6] we assume that cyclisation occurs
by initial deprotonation followed by copper-mediated oxi-
dative radical generation and then homolytic aromatic sub-
stitution.
Table 1. Optimisation of the reaction conditions for the cyclisation
of 8a to 9a.
Entry
Cu-source (eq)
Time [h] Yield of 9a [% ]
1
2
3
4
Cu(OAc)2·H2O (1 equiv.)[a]
2
2
3
3
21[c]
78
38
[b]
Cu(2-ethylhex)2 (1 equiv.)
Cu(2-ethylhex)2 (0.1 equiv.)
–
0 (decomp.)
Scheme 2. Scope of the cyclisation reaction to 3H-indoles.
[a] When toluene (at 110 °C) was used in place of mesitylene, only
1
decomposition was observed by H NMR spectroscopy. [b] Cu(2-
ethylhexanoate)2 = [Me(CH2)3CH(Et)CO2]2Cu. [c] Isolated as an
inseparable mixture of 9a and 11. According to 1H NMR spec-
troscopy after purification and the mass recovered, 9a was esti-
mated at 21% and 11 at 14%.
Using these optimal conditions, the scope of the process
in terms of substrate structure was examined (Scheme 2).
Varying the nature of the alkyl side-chain at C-3 was well
tolerated (R3 = Ph, 9b; R3 = allyl, 9c). The oxygen-contain-
ing substrate 9d, interesting for the synthesis of indoline-
type natural products such as physovenine (4; Figure 1),
cyclised in a good 63% yield. Substitution of the aromatic
ring showed that an electron-rich aniline was also well toler-
Figure 2. Crystal structure of 9h (50% probability ellipsoids).
It should be noted that the method failed for substrates
ated (9e). The alkyl group at C-3 could also be replaced by 12–14, where starting materials were recovered (Scheme 3).
another ester functionality (9f). Varying the nature of the The presence of a C-2 aryl substituent therefore appears
electron-withdrawing group at C-3 was also well tolerated crucial. In the case of 15, the starting material was con-
(9l–9m) as was the nature of the aromatic ring at C-2 (9g– sumed, but no spirocyclic 3H-indole product was isolated.
9n). It should be noted that for the first time, the CuII- For this example, steric hindrance may have been the prob-
mediated cyclisation conditions offer the possibility of lem. It should also be noted that we were unable to prepare
changing the nature of the aromatic ring at C-2 as well as cyclisation precursors in which the EWG substituent was
the electron-withdrawing group at C-3. With the exception replaced, for example, by an aromatic substituent (presum-
of 9a, all cyclised products are novel compounds and were ably due to rapid hydrolysis).
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Eur. J. Org. Chem. 2015, 2333–2336

3H- and 1H-Indoles from N-Aryl-enamines
inyl (10af) substrates delivered the cyclised products in good
yields.
Scheme 3. Substrates not affording indole products.
Given the success of the CuII route with 3H-indoles, we
briefly extended its use to prepare related 1H-indoles.[7]
Whereas classical synthetic methods such as the Fischer
indole synthesis has been used for more than a hundred
years, transition metal catalysed cyclisation of linear en-
amine precursors by a cross-dehydrogenative coupling
(CDC) process, has emerged as a powerful alternative over
the past several decades.[8] An important example was re-
ported by Glorius and co-workers, who developed a palladi-
um(II)-catalysed oxidative cyclisation reaction of N-aryl-en-
amines derived from aniline and β-dicarbonyl compounds
to afford 1H-indoles.[8i]
Scheme 4. Scope of the cyclisation reaction to 1H-indoles.
With the aim of obtaining 3-substituted indoles, we at-
tempted to apply our CuII-mediated protocol to trisubsti-
tuted enamines (which after the initial cyclisation should
spontaneously tautomerise from the 3H-indole 9aa to 1H-
indole 10aa). The reaction of readily available ethyl (2Z)-
3-phenyl-3-(phenylamino)prop-2-enoate[8i] (8aa) with Cu(2-
ethylhexanoate)2 gave the desired indole product 10aa but
only in a moderate 54% yield (Table 2, Entry 1). Switching
the copper salt from Cu(2-ethylhexanoate)2 to Cu(OAc)2·
H2O significantly increased the yield to 69% (Entry 2).
Reducing the amount of copper in the reaction dramatically
lowered the yield (Entry 3), as observed before with the ind-
olenine example 9a (Table 1, Entry 3). Also, a similar result
was observed when the reaction was carried out without
copper and only decomposition was detected (Entry 4).
Conclusions
We have developed a highly efficient oxidative coupling
process by employing inexpensive and air-stable copper
salts. The current protocol conveniently affords structurally
diverse indole derivatives including 3,3-disubstituted ind-
olenines and 3-substituted indoles from readily available an-
iline-derived enamines. Further studies to apply these pro-
cesses in target synthesis are in progress.
Experimental Section
Representative Example. Synthesis of 9a: To a stirred solution of
ethyl (2Z)-2-methyl-3-phenyl-3-(phenylamino)prop-2-enoate (8a)
(0.053 g, 0.187 mmol) in mesitylene (5 mL) was added Cu(2-ethyl-
hexanoate)2 (0.066 g, 0.187 mmol). The flask was fitted with a con-
denser and a CaCl2 drying trap. The reaction mixture was stirred
and heated to 170 °C (Drysyn heating block) for 2 h. The resulting
green solution was cooled to room temperature. NH4OH (10 mL)
was added, the aqueous phase was extracted with EtOAc (2ϫ
10 mL). The combined organic extracts were washed with H2O
(10 mL) and brine (10 mL), dried (MgSO4), filtered, and concen-
trated in vacuo. The brown residue was purified by column
chromatography (SiO2; hexane/EtOAc, 99:1) to give the title com-
pound 9a (0.041 g, 78%) as a colourless oil. Rf = 0.28 (hexane/
Table 2. Optimisation of the reaction conditions for the cyclisation
of 8aa to 10aa.
Entry
Cu source (equiv.)
Time [h]
Yield of 10aa [%]
1
2
3
4
Cu(2-ethylhex)2 (1)
Cu(OAc)2·H2O (1)
Cu(OAc)2·H2O (0.1)
–
2
2
3
2
54
69
17
0 (decomp.)
EtOAc, 9:1). IR: ν
= 2983, 2935, 1728, 1531, 1444, 1236, 1221,
˜
max
1101, 1012, 1004, 754, 728, 513 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.98–7.94 (m, 2 H, CH), 7.71 (dd, J = 7.6, 1.0 Hz, 1 H, CH),
7.49–7.45 (m, 3 H, CH), 7.42 (td, J = 7.6, 1.0 Hz, 1 H, CH), 7.40–
7.37 (m, 1 H, CH), 7.26 (td, J = 7.6, 1.0 Hz, 1 H, CH), 4.12 (dq,
J = 10.8, 7.1 Hz, 1 H, CH2), 3.97 (dq, J = 10.8, 7.1 Hz, 1 H, CH2),
1.71 (s, 3 H, CH3), 0.97 (t, J = 7.1 Hz, 3 H, CH3). 13C NMR
(100 MHz, CDCl3): δ = 178.1 (C), 171.6 (C), 154.9 (C), 141.8 (C),
132.0 (C), 131.2 (CH), 129.1 (CH), 128.9 (CH), 128.4 (CH), 126.4
Having established successful conditions for the cycli-
sation of the model system 8aa, we went on to test the sub-
strate scope using a range of enamine precursors 8ab–af. A
substrate with electron-donating substituents was prepared
and converted into the indole product (10ab; Scheme 4).
Different groups at C-2 were also tolerated. Thus, 4-substi-
tuted phenyl (10ac–10ad), 2-thiophenyl (10ae), and 4-pyrid- (CH), 121.4 (CH), 121.2 (CH), 62.2 (C), 61.9 (CH2), 21.1 (CH3),
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P. Drouhin, R. J. K. Taylor
SHORT COMMUNICATION
13.8 (CH3) ppm. MS (ESI): calcd. for C18H17NNaO2 [MNa]+
302.1151; found 302.1153; Δ = 0.5 ppm.
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CCDC-1033699 contains the supplementary crystallographic data
for this compound. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data of the prod-
1
ucts, and copies of the H and 13C NMR spectra.
Acknowledgments
We thank the University of York Wild Fund for postgraduate sup-
port (P. D.).
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Received: January 23, 2015
Published Online: March 13, 2015
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Eur. J. Org. Chem. 2015, 2333–2336