Exploring the oxidative cyclization of substituted N-aryl enamines: Pd-catalyzed formation of indoles from anilines

Article abstract of DOI:10.1002/chem.201100631

The direct Pd-catalyzed oxidative coupling of two C-H-bonds within N-aryl-enamines 1 allows the efficient formation of differently substituted indoles 2. In this cross-dehydrogenative coupling, many different functional groups are tolerated and the starting material N-aryl-enamines 1 can be easily prepared in one step from commercially available anilines. In addition, the whole sequence can also be run in a one-pot fashion. Optimization data, mechanistic insight, substrate scope, and applications are reported in this full paper. Copyright

Full text of DOI:10.1002/chem.201100631

DOI: 10.1002/chem.201100631
Exploring the Oxidative Cyclization of Substituted N-Aryl Enamines:
Pd-Catalyzed Formation of Indoles from Anilines
Julia J. Neumann,[a] Souvik Rakshit,[b] Thomas Drçge,[b] Sebastian Wꢀrtz,[c] and
Frank Glorius*[b]
À
Abstract: The direct Pd-catalyzed oxidative coupling of two C H-bonds within N-
aryl-enamines 1 allows the efficient formation of differently substituted indoles 2.
À
In this cross-dehydrogenative coupling, many different functional groups are toler-
ated and the starting material N-aryl-enamines 1 can be easily prepared in one
step from commercially available anilines. In addition, the whole sequence can
also be run in a one-pot fashion. Optimization data, mechanistic insight, substrate
scope, and applications are reported in this full paper.
Keywords: anilines · C C coupling ·
À
C H activation
palladium
·
indoles
·
Introduction
the reaction centers is not required. ꢀkermark et al.[9] and
Knçlker et al.[10] have independently reported the formation
of carbazoloquinone and carbazole derivatives by an excit-
ing Pd-catalyzed and -mediated intramolecular oxidative
Heck-type coupling (Scheme 1). Best results were obtained
Indole derivatives are widely distributed in nature[1] and are
known to be an important structural unit for the develop-
ment of pharmaceuticals,[2] agrochemicals,[3] and materials
sciences.[4] Generally, substituted indoles have been referred
to as “privileged structures” since they are capable of bind-
ing to many receptors with high affinity.[5] Among many var-
iations, 2,3-disubstituted indole substructures are widely dis-
tributed in nature as indole alkaloids and drugs, for exam-
ple, vinblastine, reserpine, okaramines, and indomethacin.
Over the last century, the synthesis of indoles has been an
important area of research for organic chemists, and several
powerful methods for the synthesis of indoles have been re-
ported.[6] However, lack of starting material availability and
functional-group tolerance often limits the generalization of
a particular indole synthesis method. The development of
mild, selective, and efficient methods for the synthesis of
such compounds is highly desirable. In this context, direct
Scheme 1. Comparison of related strategies for indole formation.
À
oxidative C C coupling by the selective activation of two
[7]
À
C H bonds is a promising synthetic strategy. In contrast to
established cross-coupling methods[8] prefunctionalization of
by employing electron-rich aniline substrates, since these re-
actions proceed by an electrophilic aromatic palladation
mechanism. However, the need for acidic reaction media
(HOAc), the rather harsh reaction conditions, and the limit-
ed scope restrict the applicability of these methods. By sig-
nificantly changing the substrates and especially the reaction
conditions, we recently developed an efficient method for
the formation of indoles by Pd-catalyzed oxidative cycliza-
tion of N-aryl enaminones.[11] This oxidative Heck-type
indole formation is more versatile than the standard Heck
reaction, obviating the need for ortho-halo anilines
(Scheme 1). In this full paper, we report on the details of
this versatile cross-dehydrogenative coupling reaction
(Scheme 1).
[a] Dr. J. J. Neumann+
Bayer CropScience AG, Alfred-Nobel-Strasse 50
40789 Monheim am Rhein (Germany)
[b] Dr. S. Rakshit,+ T. Drçge, Prof. Dr. F. Glorius
Westfꢁlische Wilhelms-Universitꢁt Mꢂnster
Organisch-Chemisches Institut, Corrensstrasse 40
48149 Mꢂnster (Germany)
Fax : (+49)251-833-3202
E-mail: glorius@uni-muenster.de
[c] Dr. S. Wꢂrtz
Archimica GmbH, Industriepark Hçchst
D569, 65926 Frankfurt am Main (Germany)
[+] These two authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100631.
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FULL PAPER
Table 1. Variation on the aromatic part of enaminones.[a]
Results and Discussion
We commenced our investigation with the cyclization of
methyl (Z)-3-(phenylamino)but-2-enoate (1a) to give the
corresponding indole 2a. Optimization reactions were car-
ried out and the best results were obtained with a catalytic
Compounds 2
Compounds 3 and 4
amount of PdACHTUNGTRENNUNG(OAc)2, CuCAHTUNGTREN(NUNG OAc)2 as the oxidant, and K2CO3
as the base in DMF. Under these conditions, conversion was
complete within 3 h at 808C or within less than 15 min at
1408C, even when only 5 mol% of PdACTHNUTRGENUG(N OAc)2 was used
(Scheme 2).[12] It is worth noting that 1a can be prepared
very easily in gram scale by condensation of methyl acetoa-
cetate and aniline[13] (both are commercially available and
cheap relative to the required starting materials necessary in
other existing methods).
[a] 1 (1.0 mmol), Cu
N
ACHTUNGTRENNUNG(OAc)2
(10 mol%), DMF (12 mL), 1408C, 30 min, isolated yield given.
[b] 1408C, 14 h. [c] 1108C, 14 h. [d] 1108C, 5 h. [e] 808C for 12 h. [f] 608C,
8 min, debrominated indole 2a as the byproduct. [h] Starting material
was TBS-protected hydroxyl-enaminone. [g] 808C, 14 h.
Scheme 2. Optimized reaction conditions.
The presence of a meta-substituent on the aniline frag-
ments can afford two regioisomeric indole products 5 and 5’.
Intriguingly, exclusive formation of the 6-substituted indole
regioisomer was observed with both the electron-withdraw-
ing acetyl and the electron-donating methoxy substituent
(Table 2, entries 1, 7). Similarly, good regioselectivities were
observed with trifluoromethyl, chloro, bromo, and methyl
substituents (Table 2, entries 2, 4, 5, 6). The presence of the
small fluoro substituent led to the nonselective formation of
the 4- and 6-substituted indole regioisomers (Table 2,
entry 3). It seems that the steric demand of the substituents
is responsible for the levels of regioselectivity obtained in
this transformation rather than their electronic character. In-
terestingly, the substrate derived from a-naphthylamine con-
With these optimized conditions in hand, we examined
the substrate scope with different substituents on the aryl
group of the enaminone (Table 1). Substrates with a variety
of electron-withdrawing and -donating substituents were
successfully converted directly into the indole products. Sen-
sitive groups like nitro, nitrile, acetyl, ester, amide (38), and
a trifluoromethyl group can be used on the aromatic part of
the enaminone derivative in moderate to good yield. Halo-
substituents on the aryl part of the enaminone were also tol-
erated under mild conditions (2j). However, debrominated
indole (2a) was also formed in small amount under these re-
action conditions. The formation of a brominated indole de-
rivative (2j) is attractive because these bromoindoles are
key intermediates in the preparation of biologically active
compounds by Suzuki–Miyaura cross-coupling reactions.[14]
Interestingly, ortho-alkyl substituted enaminones led to com-
parably higher yields than para-alkyl substituted enami-
nones (Table 1, for example, 3e compared to 2k). Similarly,
a bulky alkyl substituent at the ortho-position of the enami-
none gave a good yield (Table 1, 3g, 3h). Although the free
amine (NH2) and hydroxyl (OH)-substituted enaminones
decomposed (not shown), pivalyl-protected amine and
acetyl-protected hydroxyl-substituted enaminones gave good
yields under our optimized reaction conditions (Table 1, 2l,
2m), whereas TBS-protected hydroxyl-substituted enami-
none provided the corresponding deprotected free hydroxyl-
substituted indole under these basic conditions in good yield
(Table 1, 2n). Furthermore, methoxy-substituted enami-
nones performed well under our reaction conditions
(Table 1, 2o, 3i). The ability to vary the aniline moiety so
broadly is a noticeable attractive feature of this indole syn-
thesis.
À
taining both available a and b C H bonds underwent the
desired reaction to give only one regioisomer (5h) in excel-
lent yield (Table 2, entry 8).
The enaminone moiety was also varied successfully with
the efficient formation of different carbonyl derivatives.
Ethyl and tert-butyl ester-derived enaminones formed the
corresponding indole products smoothly under our opti-
mized reaction conditions (Table 3, entries 1–4). Interesting-
ly, ethyl (Z)-3-(phenylamino)-but-2-enoate also gave a good
yield when using cheap Cu
Concurrently, we have demonstrated
(10.0 mmol) synthesis of 6a by using 2.0 mol% Pd
catalyst and Cu(OAc)2 hydrate as an oxidant in reasonable
ACHTUNGTRENNUNG
a
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
yield. Besides ester-substituted enaminones, some nitrile-
and ketone-substituted enamines also reacted to indole
products in good yield (Table 3, entries 5, 6). Electronically
different b-substituted (CF3, iPr, OEt) enaminones were
also smoothly converted to the products under our opti-
mized reaction conditions (Table 3, entries 7–9). Notably, no
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7299

F. Glorius et al.
[a]
À
Table 2. Regioselective aromatic C H bond activation.
Table 3. Variation on enaminone part.
Entry
1
Product
Yield[b] [%]
54
Entry
Enaminone
Product
Yield [%]
1[a]
2[b]
3[c]
71
70
62
4[a]
79
69
2[c]
54
5[d]
3[d]
74[e]
6[e]
85
4[c]
5[f]
6[g]
7[b]
75
43
68
64
7[f]
80
73
73
68
8[f]
9[g]
10[h]
8[c]
85
11[i]
58
[a] 1 (1.0 mmol), CuACHTUNGTRENNUNG(OAc)2 (3.0 mmol), K2CO3 (3.0 mmol), PdACHTUNTGERN(NUGN OAc)2
(10 mol%), DMF (12 mL), 1408C, 30 min; regioisomeric ratio was calcu-
lated by GC analysis. [b] Isolated yield of the major product. [c] 808C,
14 h. [d] 1108C, 14 h. [e] Yield of inseparable regioisomeric mixture.
[f] 608C, 8 min, debrominated indole 2a as the byproduct;[g] 808C, 16 h.
12[i]
58
59
base had to be used to achieve good conversion for elec-
tron-rich a-substituted enaminone (Table 3, entry 9).[15] In-
terestingly, when using aryl substituents on the b-position of
enaminone derivatives higher temperatures and microwave
irradiation were required to achieve reasonably good yields
(Table 3, entries 10–12). Hetero biaryl compounds can also
be efficiently synthesized in moderate yield (Table 3,
entry 13).
Apparently, the N-methyl derivative of 1a decomposed
under reaction conditions and no desired product was ob-
served. This indicates the essential need of the free NH to
achieve enough reactivity for this reaction (Scheme 3).
13[j]
[a] 1 (1.0 mmol), Cu
(5 mol%), DMF (12 mL), 1408C, 15 min. [b] Cu
Cu(OAc)2. [c] 1 (10.0 mmol), Cu(OAc)2·H2O (30.0 mmol), K2CO3
(30.0 mmol), Pd(OAc)2 (2 mol%), DMF (120 mL), 1408C, 17 h.
[d] K3PO4 (1 equiv) instead of K2CO3, 1258C, 12 h. [e] 1 (1.0 mmol), Cu-
(OAc)2 (3.0 mmol), K2CO3 (3.0 mmol), Pd(OAc)2 (10 mol%), DMF
G
ACHTUNGTRENNUNG(OAc)2
AHCTUNGTRENNUNG
E
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
G
ACHTUNGTRENNUNG
(12 mL), 1408C, 24 h. [f] 1408C, 1 h. [g] 1108C, 1 h, no base was used.
[h] 1808C (microwave), 1 h. [i] 1608C (microwave), 1 h. [j] 1108C, 14 h.
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Pd-Catalyzed Formation of Indoles from Anilines
FULL PAPER
the efficiency of this reaction, we performed a 5.0 mmol
scale reaction with methyl 1h by using 5.0 mol% PdACHTUNGTRENNUNG(OAc)2
as the catalyst and K3PO4 as the base in 79% isolated yield.
Surprisingly, the combination of CuBr2 and K3PO4 did not
give any detectable amount of the desired product.
Scheme 3. Cyclization of the N-methyl derivative of 1a.
A few attempts were made to lower the amount of Cu-
AHCTUNGTRENNUNG
(OAc)2 and to use air or oxygen as the terminal oxidant.[17]
In our previous optimization, we had observed that a less
polar solvent like toluene is less efficient for this transfor-
mation relative to an aprotic polar solvent like DMF.[11] But,
no study was performed with other bases (except carbo-
nates) when using DMF to get better reactivity towards the
desired indole product. In addition, the carbonate base
leads to a buildup of pressure (CO2), which might pose a
significant danger for large-scale reactions. Thus, we com-
menced our reoptimization study to find other suitable sol-
vents and cheaper oxidants and bases. To optimize the reac-
tion (Z)-methyl 3-[(4-fluorophenyl)amino]but-2-enoate (1h)
was used as the starting material and quantitative reaction
control by 19F NMR spectroscopy was performed based on
5-fluoro-substituted indole derivative 2h. Firstly, DMA
(N,N-dimethylacetamide) and NMP (N-methylpyrrolidone)
showed reactivity similar to the standard reaction conditions
(Table 4, entries 2, 3), whereas other coordinating polar sol-
vents, such as iPrCN, dioxane, or DMSO, gave only very
However, unfortunately none of these experiments met with
success.[12] Finally, we intended to use mono-hydrated Cu-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
out any moisture precaution. Under these conditions, we
have successfully shown the formation of our desired indole
product in good yield (Scheme 4).
Scheme 4. Reoptimized reaction.
From a synthetic point of view, to make this overall ap-
proach to indoles even more attractive, we explored their
formation through a one-pot reaction sequence that omits
the isolation of the enaminone intermediates.[18] Thus, substi-
tuted anilines were condensed at room temperature with
methyl acetoacetate in the presence of InBr3 (1.0 mol%) to
give the corresponding enamine carboxylates,[19] which un-
derwent subsequent cyclization under the standard condi-
tions to give the desired indole products in good yield
(Scheme 5).
poor yields (Table 4, entries 4–6).[16] Replacing Cu
ACTHNUTRGNEN(UG OAc)2 by
other Fe and Cu-based oxidants also did not work well, but
CuBr2 gave moderate yield. The role of the base is essential;
strong bases like NaOH gave comparable yields, whereas
KOtBu was not efficient under these conditions. The best
result was obtained with K3PO4 (73% NMR yield). To show
Table 4. Reoptimization of the reaction conditions.[a]
Entry
Variation from standard conditions
Yield [%]
1
none
58
2
3
4
5
DMA instead of DMF
NMP instead of DMF
iPrCN instead of DMF
Dioxane instead of DMF
DMSO instead of DMF
57
56
Scheme 5. One-pot synthesis of indole from aniline.
1[16]
3
13
6
To probe the role of the CuII salt, the reaction was per-
7[b]
8[b]
9[b]
10[b]
11[b]
12[b]
13[b]
14[b]
15[b]
Fe
FeCl3 instead of Cu
Cu(acac)2 instead of Cu
CuBr2 instead of Cu(OAc)2
CuO instead of Cu(OAc)2
G
E
2
0
3
48
2
69
18
formed by using PdACTHNUTRGNEUNG(OAc)2 (20 mol%) as the catalyst with
G
K2CO3 (3.0 equiv) as the base at 1108C for 1 h (without CuII
R
R
1
salt) leading to 15% H NMR spectroscopic yield. After this
N
time, addition of CuACHTNUGTRNEUNG(OAc)2 (3.0 equiv) to the mixture and
NaOH instead of K2CO3
prolonged heating for 12 h at 1108C resulted in continued
KOtBu instead of K2CO3
[c]
1
K3PO4 instead of K2CO3
73 (79)[d]
0
turnover and 43% yield determined by H NMR spectrosco-
py.[12] This experiment suggests that Cu
ACHTUNGTRENNUNG
CuBr2 as oxidant and K3PO4 as base
[a] Standard reaction conditions: 1h (0.25 mmol), Cu
K2CO3 (0.75 mmol), Pd(OAc)2 (10 mol%), DMF (3 mL), the yield was
determined by 19F NMR spectroscopy. [b] 1208C was used. [c] The K3PO4
employed was pestled and dried. [c] 1h (5.0 mmol), Cu(OAc)2
(15.0 mmol), K3PO4 (15.0 mmol), Pd(OAc)2 (5.0 mol%), DMF (60 mL),
ACHTUNGRTEN(NGNU OAc)2 (0.75 mmol),
ACHTUNGTRENNUNG
AHCTUNGRTEG(NNUN OAc)2 just acts as a terminal oxidant to achieve the turn-
over in the catalytic cycle.[20]
AHCTUNGTRENNUNG
À
To learn about the C H activation step, an intramolecular
AHCTUNGTRENNUNG
808C for 66 h, isolated yield given.
kinetic isotope effect of enaminone (8) was determined.
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F. Glorius et al.
Scheme 8. Synthesis of indole-derived free acid.
Scheme 6. Determination of the intramolecular kinetic isotope effect.
and 7b to give 3-unsubstituted indole 12 (Scheme 9), which
is a very valuable building block for medicinal chemistry
and natural-product synthesis.[2,3] This further functional
group modification shows the potential application of this
method.
This intramolecular kinetic isotope effect kH/kD =4.6 sug-
À
gested that the C H activation step does not proceed
through an electrophilic aromatic palladation (Scheme 6).
Furthermore, competition experiments were carried out
between electronically different para-substituted substrates
1 (Cl with H and Me with OMe). These set of experiments
showed that electron-donating groups in the para-position
slow down this transformation.[12] This observation is in
agreement with a mechanism involving s-bond metathesis
or base-assisted deprotonation, but not with an electrophilic
aromatic palladation.[21]
N-Aryl enamine carboxylates tend to react with electro-
philes at the a-C atom;[22] similar reactivity was also report-
ed recently for a palladium-catalyzed coupling of enami-
nones with aryl borates.[23] Therefore, a plausible mechanism
begins with an electrophilic palladation of the nucleophilic
enamine,[24] followed by deprotonation (Scheme 7). The re-
Scheme 9. Synthesis of 3-unsubstituted indole. TFA=trifluoroacetic acid.
sulting palladium complex A is suitable for intramolecular
Conclusion
[25]
À
C H activation, such as s-bond metathesis or base-assist-
ed deprotonation.[26] Subsequent reductive elimination gen-
erates the indole product and a Pd0 complex that can be re-
oxidized to the PdII complex by the terminal oxidant Cu-
We have developed an efficient and broadly applicable
direct oxidative synthesis of indoles from commercially
available anilines. This concept is broadly applicable in dif-
ferent systems towards the synthesis of 2,3-disubstituted in-
doles. In the aftermath of our communication,[11] this strat-
egy was skillfully utilized by the groups of Jiao, Zhao,
Cacchi, and Liang.[27] Their reported methods represent at-
tractive indole formations with attractive features, such as
using no toxic Pd catalyst or utilizing oxygen as the terminal
oxidant.[27] All these studies provide new or improved syn-
thetic routes to valuable indoles and new preparative appli-
cations for biologically active indole-based molecules. Fur-
thermore, a one-pot reaction sequence enables rapid access
to indoles from commercially available anilines.
ACHTUNGTRENNUNG
ceeds under mild hydrogenolytic conditions to provide the
free carboxylic acid in excellent yield (Scheme 8).
To further demonstrate the synthetic utility of the indole
products, we carried out decarboxylation reactions with 2h
Experimental Section
General procedure: Methyl (Z)-3-(phenylamino)-but-2-enoate (1a;
191 mg, 1 mmol) was stirred in DMF (12 mL) together with Pd
ACHTUNGTRENNUNG(OAc)2
(22.5 mg, 10 mol%), Cu(OAc)2 (545 mg, 3 mmol), and K2CO3 (415 mg,
AHCTUNGTRENNUNG
3 mmol) at 808C under an atmosphere of argon. After completion of the
reaction (as indicated by TLC, GC, or GCMS), the reaction mixture was
cooled to room temperature, diluted with EtOAc (15 mL), and filtered
through a short pad of silica, which was then washed with EtOAc
(60 mL). Removal of the solvent in vacuo and purification of the residue
by flash chromatography (SiO2, pentane/EtOAc 5:1) provided indole 2a
(136 mg, 0.72 mmol, 72%) as an orange solid.
Scheme 7. Mechanism for palladium-catalyzed indole synthesis from en-
aminone.
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Pd-Catalyzed Formation of Indoles from Anilines
FULL PAPER
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Acknowledgements
Generous financial support by the NRW Graduate School of Chemistry,
the Fonds der Chemischen Industrie, the European Research Council,
and the Deutsche Forschungsgemeinschaft is gratefully acknowledged.
The research of F.G. has been supported by the Alfried Krupp Prize for
Young University Teachers of the Alfried Krupp von Bohlen und Hal-
bach Foundation.
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[18] As an example of the value of this method, we quote the cost of
purchasing the starting materials and the product in 99% purity
from Sigma–Aldrich for one transformation: aniline: 25.70 Euro per
L; ethyl acetoacetate: 38 Euro per 1 kg; ethyl-2-methylindole-3-car-
boxylate: 67.20 Euro per g.
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[24] An initial olefin-palladium p complex should also be considered,
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[27] Following our initial report on this indole formation, a number of
research groups reported powerful related methods: Pd-catalyzed:
a) Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y. Cui, N. Jiao, Angew.
Chem. 2009, 121, 4642; Angew. Chem. Int. Ed. 2009, 48, 4572; by
using a hypervalent iodine reagent, not transition-metal-catalyzed:
b) W. Yu, Y. Du, K. Zhao, Org. Lett. 2009, 11, 2417; Cu-catalyzed:
c) R. Bernini, G. Fabrizi, A. Sferrazza, S. Cacchi, Angew. Chem.
2009, 121, 8222; Angew. Chem. Int. Ed. 2009, 48, 8078; Fe-catalyzed:
d) Z.-H. Guan, Z.-Y. Yan, Z.-H. Ren, X.-Y. Liu, Y.-M. Liang, Chem.
Commun. 2010, 46, 2823.
Received: February 25, 2011
Published online: May 12, 2011
Chem. Eur. J. 2011, 17, 7298 – 7303
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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