Mechanistic study on the palladium(II)-catalyzed synthesis of 2,3-disubstituted indoles under aerobic conditions: Anion effects and the development of a low-catalyst-loading process

Article abstract of DOI:10.1002/chem.201403612

As a result of detailed mechanistic and kinetic studies, we have proposed that PdX₂-catalyzed oxidative coupling of o-alkynylanilines 1 with terminal alkynes 2 under aerobic conditions is initiated by aminopalladation of 1 followed by ligand exchange of the resulting σ-indolylpalladium(II) complex with 2, reductive elimination and N-demethylation. Side reactions associated with intermediates on the way to 2,3-disubstituted indoles 3 were identified, and the roles of acetate and iodide in channeling the reaction towards the desired product were established. Based on kinetic and spectroscopic studies, the soluble iodide-ligated Pd⁰ species was proposed to be the resting state of the catalyst and its oxidation to active Pd^II species was the turnover-limiting step. Catalytic conditions with low loading of Pd(OAc)₂ (0.0005 to 0.001 equiv) were subsequently developed.

Full text of DOI:10.1002/chem.201403612

DOI: 10.1002/chem.201403612
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&
Synthetic Methods
Mechanistic Study on the Palladium(II)-Catalyzed Synthesis of 2,3-
Disubstituted Indoles Under Aerobic Conditions: Anion Effects
and the Development of a Low-Catalyst-Loading Process
Bo Yao, Qian Wang, and Jieping Zhu*[a]
Abstract: As a result of detailed mechanistic and kinetic
studies, we have proposed that PdX2-catalyzed oxidative
coupling of o-alkynylanilines 1 with terminal alkynes 2 under
aerobic conditions is initiated by aminopalladation of 1 fol-
lowed by ligand exchange of the resulting s-indolylpalladiu-
m(II) complex with 2, reductive elimination and N-demethy-
lation. Side reactions associated with intermediates on the
way to 2,3-disubstituted indoles 3 were identified, and the
roles of acetate and iodide in channeling the reaction to-
wards the desired product were established. Based on kinet-
ic and spectroscopic studies, the soluble iodide-ligated Pd0
species was proposed to be the resting state of the catalyst
and its oxidation to active PdII species was the turnover-lim-
iting step. Catalytic conditions with low loading of Pd(OAc)2
(0.0005 to 0.001 equiv) were subsequently developed.
Introduction
The catalytic system [Pd(OAc)2(0.05–0.1 equiv)/DMSO/O2],
developed independently by Larock[10] and Hiemstra[11] in the
mid-1990s,[12] is one of the simplest yet most effective oxida-
tive palladium catalyst systems available, and a number of
transformations such as oxidation of alcohols, difunctionaliza-
tion of alkenes, and CÀH functionalization have been devel-
oped based on this catalytic combination. Bꢀckvall has devel-
oped an efficient PdII-quinone-sulfoxide catalytic system for
acetoxylation of alkenes.[13] Recently, we have become interest-
ed in PdII-catalyzed difunctionalization of alkynes and found
that by adding one equivalent each of acetic acid (HOAc) and
tetra-n-butylammonium iodide (nBu4NI) into the Larock–Hiem-
stra catalytic system, it is possible to introduce two nucleo-
philes across a triple bond (Scheme 1a).[14,15] One representa-
tive example is the PdII-catalyzed cyclizative cross-coupling of
o-alkynylanilines 1 with terminal alkynes 2 for the synthesis of
1,2,3-trisubstituted 3-alkynylindoles 3 (Scheme 1b).[14b] This re-
action displayed broad substrate scope and tolerated
The indole nucleus is an important heterocycle that is found in
many bioactive natural products, pharmaceuticals, and agro-
chemicals.[1] The synthesis and functionalization of indoles
have attracted the attention of chemists for over a century.[2]
Among transition-metal-catalyzed transformations,[3] Pd0-cata-
lyzed reactions such as the Cacchi indole synthesis[4] and the
Larock indole synthesis,[5] developed 20 years ago, have found
extensive applications in the synthesis of bioactive indole-con-
taining compounds. In contrast, only a few PdII-catalyzed aero-
bic oxidative protocols have been developed for the synthesis
of this important heterocycle.[3j–n]
Many PdII-catalyzed aerobic oxidative reactions, represented
by the Wacker process,[6] have been developed.[7] The discovery
that coordinating solvents and oxidatively stable ligands are
capable of stabilizing and accelerating the oxidation of Pd0 to
PdII species represented a major breakthrough in this field.[8]
However, the development of catalytic processes with high
catalyst turnover efficiency remained a challenging task due to
the limited choice of effective ligands under oxidative condi-
tions. Indeed, in contrast to Pd0-catalyzed cross-coupling reac-
tions under inert atmosphere, examples of oxidative palladium
catalysis[7a] with catalyst loading of less than 1.0 mol% are
rare.[9]
[a] Dr. B. Yao, Dr. Q. Wang, Prof.Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN BCH 5304, 1015 Lausanne (Switzerland)
Fax: (+41)21-693-97-40
E-mail: jieping.zhu@epfl.ch
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403612.
Scheme 1. Oxidative palladium catalysis: adding two nucleophiles across al-
kynes.
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a number of functional groups. However, the exact reaction se-
quence of this complex domino process was not clear,[16] and
the catalyst loading (0.05 equiv) was relatively high. In this
paper, we report the results of our detailed mechanistic and ki-
netic studies, which have allowed us to determine the exact re-
action sequence, to uncover the important roles of acetate
and iodide, as well as to establish the catalyst resting state. As
a result of this mechanistic study, catalytic conditions with
much reduced loading of palladium acetate (0.0005–
0.001 equiv) were subsequently developed.
These results indicated the critical importance of AcOÀ in this
transformation, most probably in the ligand-exchange step.
Indeed, AcOÀ in DMSO, being a much stronger base than ani-
line,[18] is able to deprotonate the Pd-coordinated terminal
alkyne. The reaction between 4b (X=OAc) and 2a in
[D6]DMSO proceeded smoothly to afford indole 3a (Scheme 3,
Results and Discussion
Study on s-indolylpalladium complexes: determining the
reaction sequence and roles of anions
The reaction of N,N-dimethyl-2-(p-tolylethynyl)aniline (1a) and
4-ethynyltoluene (2a) in the presence of PdI2, Pd(TFA)2, and
Pd(OAc)2 under otherwise standard conditions afforded the 3-
alkynyl indole 3a (R1 =R2 =p-tolyl) in yields of 8, 14, and 66%,
respectively. To gain insight into this counterion effect and to
dissect the reaction sequence, we set out to inspect the indi-
vidual elementary steps of this domino process. Mixing 1a
with a stoichiometric amount of palladium salts PdX2 in
[D6]DMSO at room temperature provided the corresponding s-
indolylpalladium(II) complexes 4 in essentially quantitative
yield, regardless the nature of the counterion (X=I, OAc,
CF3CO2; Scheme 2a).[17] Therefore, the nature of anions (XÀ) did
not influence the outcome of the aminopalladation step,
which has previously been considered as a possible initiation
step.[14b]
Scheme 3. Dissecting the reaction mechanism.
pathway a) and 1a (Scheme 3, pathway b) in 75% yield as
a 1:1 mixture. Complex 4 is relatively stable in the absence of
terminal alkyne 2a, therefore, we suspected that 1a resulted
from the retro-aminopalladation of intermediate 5, which is
a ligand-exchange product between 4b and 2a. Interestingly,
this apparently competitive retro-aminopalladation process
was completely suppressed by adding four equivalents of
nBu4NI to the reaction mixture. We tentatively attributed the
role of IÀ to forming an ionic intermediate of type [R1R2PdI]À,
which is conducive to reductive elimination.[19,20] Finally, simply
mixing 4c (X=CF3CO2) with 2a in [D6]DMSO at room tempera-
ture afforded rapidly indolium trifluoroacetate 6 (X=CF3CO2),
which was slowly converted into indole 3a (18% after 2.5 h).
Addition of iodide or acetate to the above reaction mixture ac-
celerated the N-demethylation step, in accordance with their
increased nucleophilicity.[21]
The reaction of these complexes with terminal alkyne 2a
was then examined. No reaction took place when 2a was
added to a solution of 4a (X=I) in [D6]DMSO. However,
adding Et4NOAc (2.0 equiv) to the above mixture triggered the
coupling reaction to furnish 3a in 95% yield (Scheme 2b).
Consistent with the aforementioned observations, we con-
cluded that coupling of 1a with 2a proceeded through the re-
action sequence: aminopalladation/ligand exchange/reductive
elimination/N-demethylation.[22] The presence of AcOÀ is crucial
for the ligand exchange (4 to 5) and N-demethylation (6 to 3)
by virtue of its basicity and nucleophilicity, whereas IÀ effec-
tively suppressed the retro-aminopalladation of intermediate 5
and accelerated the N-demethylation step. It is interesting to
note that heating to 808C was required to complete the reac-
tion when a catalytic amount of Pd(OAc)2 was used (standard
conditions). However, the aminopalladation of 1a and the sub-
sequent coupling of the resulting s-indolylpalladium(II) com-
plex 4b (X=OAc) with 2a took place smoothly at room tem-
perature with a stoichiometric amount of Pd(OAc)2. This obser-
Scheme 2. Synthesis and reactivity of s-indolylpalladium(II) complexes 4.
[a] Et4NOAc (2.0 equiv) was added 5 min after mixing 2a and 4a. [b] nBu4NI
(4.0 equiv) was added to 4b before 2a (1.0 equiv). [c] 6 was transformed
into 3a with 18% conversion after 2.5 h.
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vation has important mechanistic implications regarding the
turnover-limiting step of the process (see below).
Control experiments under inert atmosphere: role of
acetate
To explore further the anion effect, the following control ex-
periments were designed and performed to examine the first
turnover efficiency of the reaction. Firstly, the reaction of 1a
with 2a in the presence of PdI2 (0.05 equiv) under inert atmos-
phere at 808C for 60 min afforded 3,3’-bisindole 7a in 4.8%
yield and a trace amount of 3a (Scheme 4). It is difficult for
Scheme 4. PdI2-mediated reaction between 1a and 2a under anaerobic con-
1
ditions. The yield was calculated based on H NMR spectroscopic analysis by
using nBu4NI as internal standard.
Figure 1. The effect of [Pd(OAc)2] on the yield of 3a (A) and selectivity 3a/
7a (B) at the first turnover of the reaction under argon. Reaction conditions:
[1a]=100.0 mm, [2a]=200.0 mm, nBu4NI (100.0 mm), HOAc (100.0 mm) in
DMSO at 808C, argon, 10.0 min.
ligand exchange between 4a (X=I) and terminal alkyne 2a to
occur in the absence of a base, therefore, the s-indolylpalladiu-
m(II) complex underwent dimerization leading to 7a
(Scheme 3, pathway c). Significantly, subsequent exposure of
the above reaction mixture to air atmosphere (22 min) pro-
duced 3a in 15% yield without concurrent generation of 7a
(Scheme 4). Therefore, the Pd0 species generated under inert
atmosphere was readily oxidized, in the presence of HOAc and
dioxygen, to PdII species, which can then selectively catalyze
the formation of 3a at the expense of 7a.
Secondly, the reaction between 1a and 2a in the presence
of different concentrations of Pd(OAc)2 was carried out under
an inert atmosphere. By quantitative analysis of the reaction
mixture, the yields of 3a based on [Pd(OAc)2] were calculated.
The results showed that higher loading of Pd(OAc)2 led to
lower yield of 3a but with increased selectivity of 3a versus
7a (Figure 1). However, the formation of 3,3’-bisindole 7a was
completely inhibited and the yield of 3a was almost identical
at different [Pd(OAc)2] (from 0.5 to 3 mm) when the above re-
actions were performed in the presence of nBu4NOAc
(63.0 mm, Figure 2). These results confirmed that it was the
counterion rather than the amount of Pd that influenced prod-
uct selectivity.
Figure 2. Investigation of the first turnover of the reaction between 1a and
2a under inert atmosphere. Reaction conditions: [1a]=100.0 mm,
[2a]=200.0 mm, [nBu4NI]=100.0 mm, [HOAc]=100.0 mm, without
nBu4NOAc (squares) or with nBu4NOAc (63.0 mm) (circles) in DMSO, 808C,
argon, 10.0 min. Yield was normalized based on the amount of Pd(OAc)2
used: yield of 3a=[3a]/[Pd(OAc)2].
was lower than 0.06 mm with substrate concentration of
100 mm (Figure 3) and
a saturation kinetics of 3a vs.
[Pd(OAc)2] was observed. The presence of an induction time at
low catalyst loading indicated that a real active PdII catalyst
must be generated before the start of the catalytic process,
whereas at higher loading, the active species was generated
rapidly enough to obscure this phenomenon.
Reaction kinetics: determining the turnover-limiting step
and the catalyst resting state
Having established the importance of the iodide and acetate
anions in the coupling reaction of 1a with 2a, the reaction ki-
netics was then examined by employing the initial rates
method. An induction period was observed when [Pd(OAc)2]
In the presence of Pd(OAc)2 (5.0 mm), the kinetic data
showed that the initial reaction rate for the formation of 3a
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Figure 3. Observation of induction periods at low catalyst concentrations
(<0.06 mm). Reaction conditions: [1a]=100.0 mm, [2a]=200.0 mm,
[nBu4NI] = 100.0nm, [HOAc]=100.0 mm, DMSO (Vtotal =1.0 mL), 808C, air
(1 atm), stirring speed=900 rpm. [Pd(OAc)2]=0.01–0.1 mm.
was independent of [1a] and [2a] (Figure 4A and B), but had
a linear relationship with {[nBu4NI]4} (Figure 4C). These results
indicated that iodide, but not 1a or 2a, was involved in the
turnover-limiting step. The initial rate of 3a formation showed
first-order dependence on [Pd(OAc)2] when the concentration
of catalyst was low {0.01–0.04 mm, [1a]=100 mm}[23] (insert in
Figure 4D) and pseudo-zero-order dependence on [Pd(OAc)2]
when its concentration was higher than 0.3 mm (Figure 4D).
These observations were understandable assuming that a real
active PdII catalyst was generated before the start of the cata-
lytic process and most probably, the catalyst resting state was
the stabilized Pd0 species[24] and that its oxidation to active PdII
catalyst was the turnover-limiting step. The last point is also in
accord with the observation that the domino process took
place smoothly at room temperature when a stoichiometric
amount of Pd(OAc)2 was used.
Further evidence for the assumption that Pd0 can be a reser-
voir of the catalytically active PdII species was provided by the
fact that a Pd0 precatalyst can catalyze the reaction. Thus, the
reaction between 1a and 2a in the presence of [Pd2(dba)3]
(0.025 equiv) or heterogeneous Pd/C (0.005 equiv), under oth-
erwise standard conditions, afforded indole 3a in yields of 53
and 91%, respectively (Scheme 5).[25] It is interesting to note
that low loading of Pd/C (0.005 equiv) gave a better yield of
3a than higher loading of catalyst (0.05 equiv), in analogy to
the reaction catalyzed by Pd(OAc)2.
Figure 4. Kinetic dependence of the initial rate of Pd(OAc)2-catalyzed oxida-
tive cross-coupling of 1a with 2a on A) the concentration of 1a, B) the con-
centration of 2a, and C) the concentration of {[nBu4NI]4}. Reaction condi-
tions: [HOAc]=100.0 mm, DMSO (Vtotal =1.0 mL), 808C, air (1 atm), stirring
speed=900 rpm. (A): [Pd(OAc)2]=5.0 mm, [2a]=200.0 mm,
[nBu4NI]=100.0 mm; (B): [Pd(OAc)2]=5.0 mm, [1a]=100.0 mm,
[nBu4NI]=100.0 mm; (C): [Pd(OAc)2]=5.0 mm, [1a]=100.0 mm,
[2a]=200.0 mm; D): [1a]=100.0 mm, [2a]=200.0 mm, [nBu4NI]=100.0 mm,
[Pd(OAc)2]=0.01–1.0 mm.
Test experiments: determining the homogeneity of the
active catalyst
To further explore the nature of this catalytic process, filtration
experiments and Hg tests were performed.[26] The hot reaction
mixture of 1a and 2a catalyzed by Pd(OAc)2 was filtered
through Celite at 7% conversion and the filtrate was moni-
tored for further conversion. It was observed that the reaction
in the filtrate continued to progress as usual, indicating that
the reaction is not catalyzed by heterogeneous Pd-species.
One catalytic turnover was observed when Hg (100.0 equiv)
was added to the reaction mixture at the start of the reaction.
On the other hand, addition of Hg (100.0 equiv) to an ongoing
reaction led to immediate inhibition of the reaction (Figure 5).
These results suggested that the reaction might follow a Pd0/
PdII catalytic cycle and that the catalyst resting state is a Pd0
species.[27,28]
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preparation using MeOH as the diluting solvent.[30] Indeed,
analysis in situ by dynamic light scattering (DLS) failed to pro-
vide any evidence for the existence of particles in the reaction
mixture of 1a with 2a performed under the optimized condi-
tions. Combining the results of kinetic studies, test experi-
ments, TEM analysis, and DLS analysis, we hypothesized that
the catalyst resting state might be soluble iodide-ligated Pd0
species[19] that are further stabilized by the solvent (DMSO),[24]
and the ammonium salt.[31] Besides dioxygen, a trace amount
of I2 generated in situ by oxidation of iodide, may also serve as
an oxidant.[19c]
Scheme 5. Cross-coupling cyclization of 1a with 2a by using [Pd2(dba)3] or
heterogeneous Pd/C as precatalysts.
Development of a low-catalyst-loading process
The observed kinetic saturation of 3a formation versus
[Pd(OAc)2], the formation of apparently very stable Pd0 species
as resting catalytic species, together with other results ob-
tained in the aforementioned mechanistic and kinetic studies
prompted us to conclude that cross-coupling cyclization be-
tween 1 and 2 might proceed under much reduced PdII cata-
lyst loading. This prediction was borne out experimentally. As
shown in Scheme 6, the reactions of o-alkynylanilines 1 with
terminal alkynes 2 in the presence of 0.0005 equiv (R1 =aryl) or
0.001 equiv (R1 =alkyl) Pd(OAc)2 delivered 3 in good to excel-
lent yields (Scheme 6).[32] To our knowledge, this is the lowest
reported Pd(OAc)2 loading for oxidative palladium catalysis.
Figure 5. Reaction inhibition with the addition of Hg (100.0 equiv) at t=0
(dash) and 30.0 min (dot). Reaction conditions: [1a]=100.0 mm,
[2a]=200.0 mm, [nBu4NI]=100.0 mm, [HOAc]=100.0 mm, [Pd-
(OAc)2]=5.0 mm, Hg=50.0 mg, DMSO (Vtotal =0.5 mL), 808C, air (1 atm), stir-
ring speed=1500 rpm.
Transmission electron microscopy (TEM) images obtained
from the Pd(OAc)2-catalyzed reaction of 1a with 2a under the
optimized conditions at t=3.0 min showed very few particles
of approximately 1–2 nm (Figure 6).[29] Although nanoparticles
were indeed observed from TEM, it could not be concluded
that they were formed in the reaction mixture because the few
particles observed in TEM images could result from sample
Figure 6. TEM image of palladium particles at t=3.0 min. Reaction condi-
tions: [1a]=100.0 mm, [2a]=200.0 mm, [nBu4NI]=100.0 mm,
[HOAc]=100.0 mm, [Pd(OAc)2]=5.0 mm, DMSO (Vtotal =0.5 mL), 808C, air
(1 atm).
Scheme 6. PdII-catalyzed cross-coupling cyclization of o-alkynylanilines with
terminal alkynes at low catalyst loading. All reactions were performed in
a vial under air atmosphere. [a] 0.0005 equiv Pd(OAc)2. [b] 0.001 equiv
Pd(OAc)2.
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Conclusion
Acknowledgements
The data assembled in this mechanistic study allowed us to
formulate a complete mechanistic picture of the PdX2-cata-
lyzed oxidative coupling of 1 and 2 to indole 3. We propose
that the reaction was initiated by aminopalladation of 1, fol-
lowed by ligand exchange, reductive elimination, and N-deme-
thylation. The side reactions associated with intermediates
such as dimerization of s-indolylpalladium(II) complex 4 and
retro-aminopalladation of putative intermediate 5,[33] were
identified and the roles of acetate and iodide to channel the
reaction towards the desired product were established. Based
on kinetic and spectroscopic studies, we also hypothesized
that soluble iodide-ligated Pd0 species might be the resting
state of the catalyst, and its oxidation to active PdII species was
the turnover-limiting step. As a result of this mechanistic study,
conditions with low loading of Pd(OAc)2 (0.0005 to
0.001 equiv) were developed. An in-depth understanding of
this cross-coupling cyclization reaction thus provides a valuable
basis for the further development of this type of oxidative Pd
catalysis.
We thank the EPFL (Switzerland), the Swiss National Science
Foundation (SNSF), and the Swiss National Centers of Compe-
tence in Research NCCR Chemical Biology for financial support.
Keywords: aerobic · anion effect · indoles · low catalyst
loading · palladium · reaction mechanisms
[1] a) The Chemistry of Indoles (Ed.: R. J. Sundberg), Academic Press,
London, 1996; b) J. A. Joule, Indole and its Derivatives in Science of Syn-
thesis:Houben-Weyl Methods of Molecular Transformations, Category 2,
Vol. 10 (Ed.: E. J. Thomas), Thieme, Stuttgart, 2000, Chapter 10.13.
[2] For recent reviews on the syntheses of indoles, see: a) G. Zeni, R. C.
Larock, Chem. Rev. 2004, 104, 2285–2309; b) S. Cacchi, G. Fabrizi, Chem.
Rev. 2005, 105, 2873–2920; c) G. R. Humphrey, J. T. Kuethe, Chem. Rev.
2006, 106, 2875–2911; d) L. Ackermann, Synlett 2007, 507–526; e) K.
Krꢃger, A. Tillack, M. Beller, Adv. Synth. Catal. 2008, 350, 2153–2167;
f) N. T. Patil, Y. Yamamoto, Chem. Rev. 2008, 108, 3395–3442; g) J. Bar-
luenga, F. Rodrꢄguez, F. J. FaÇanꢅs, Chem. Asian J. 2009, 4, 1036–1048;
h) G. Palmisano, A. Penoni, M. Sisti, F. Tibiletti, S. Tollari, K. M. Nicholas,
Curr. Org. Chem. 2010, 14, 2409–2441; i) S. A. Patil, R. Patil, D. D. Miller,
Curr. Med. Chem. 2011, 18, 615–637; j) S. Cacchi, G. Fabrizi, A. Goggia-
mani, Org. Biomol. Chem. 2011, 9, 641–652; k) S. Cacchi, G. Fabrizi,
Chem. Rev. 2011, 111, 215–283; l) D. F. Taber, P. K. Tirunahari, Tetrahedron
2011, 67, 7195–7210.
[3] Selected examples, see: a) P. S. Baran, B. D. Hafensteiner, N. B. Ambhai-
kar, C. A. Guerrero, J. D. Gallagher, J. Am. Chem. Soc. 2006, 128, 8678–
8693; b) Y. Jia, J. Zhu, J. Org. Chem. 2006, 71, 7826–7834; c) Z. Xu, W.
Hu, F. Zhang, Q. Li, Z. Lu, L. Zhang, Y. Jia, Synthesis 2008, 3981–3987;
d) D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess, K. Fagnou, J. Am.
Chem. Soc. 2008, 130, 16474–16745; e) R. Bernini, G. Fabrizi, A. Sferraz-
za, S. Cacchi, Angew. Chem. 2009, 121, 8222–8225; Angew. Chem. Int.
Ed. 2009, 48, 8078–8081; f) Y. Tan, J. F. Hartwig, J. Am. Chem. Soc. 2010,
132, 3676–3677; g) S. G. Newman, M. Lautens, J. Am. Chem. Soc. 2010,
132, 11416–11417; h) A. Wetzel, F. Gagosz, Angew. Chem. 2011, 123,
7492–7496; Angew. Chem. Int. Ed. 2011, 50, 7354–7358; i) L. Acker-
mann, A. V. Lygin, Org. Lett. 2012, 14, 764–767; PdII-catalyzed indole
synthesis under aerobic conditions: j) S. Wꢃrtz, S. Rakshit, J. J. Neumann,
T. Drçge, F. Glorius, Angew. Chem. 2008, 120, 7340–7343; Angew. Chem.
Int. Ed. 2008, 47, 7230–7233; k) Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y.
Cui, N. Jiao, Angew. Chem. 2009, 121, 4642–4646; Angew. Chem. Int. Ed.
2009, 48, 4572–4576; l) Y. Wei, I. Deb, N. Yoshikai, J. Am. Chem. Soc.
2012, 134, 9098–9101; m) L. Ren, Z. Shi, N. Jiao, Tetrahedron 2013, 69,
4408–4414; n) T. Piou, L. Neuville, J. Zhu, Tetrahedron 2013, 69, 4415–
4420.
Experimental Section
Experimental details for kinetic study
The initial rates method was used for the kinetic study. The reac-
tion of N,N-dimethyl-ortho-(para-tolylethynyl)aniline (1a) with para-
tolylacetylene (2a) was chosen as the model reaction for kinetic
studies. Stock solutions of 1a, 2a, nBu4NI, HOAc, and Pd(OAc)2 in
DMSO were prepared freshly just before use. The reaction was con-
ducted in a 5 mL reaction tube without a cap (open to air atmos-
phere). The tube was heated in an aluminum block at 808C. When
the reaction started, a reaction aliquot (50–100 mL) was sampled by
using a 100 mL microsyringe every 3–15 min. The samples were im-
mediately treated with water (2 mL) and extracted with diethyl
ether (3ꢂ2 mL). The organic extracts were filtered through a pad
of anhydrous sodium sulfate and silica gel, and concentrated
under reduced pressure. Each residue was dissolved in CDCl3
(500 mL) with PhNBn2 (1 mgmLÀ1) as the internal standard, and the
1
solution was submitted to H NMR spectroscopic analysis. The con-
centration of the product 3a was calculated based on 1H NMR
spectroscopic analysis. For each reaction, 4–6 data points between
2–12% conversions were collected to calculate the initial rate for
3a formation by linear least squares fitting technique.
[4] a) A. Arcadi, S. Cacchi, F. Marinelli, Tetrahedron Lett. 1992, 33, 3915–
3918; b) S. Cacchi, G. Fabrizi, P. Pace, J. Org. Chem. 1998, 63, 1001–
1011; c) for a review, see: G. Battistuzzi, S. Cacchi, G. Fabrizi, Eur. J. Org.
Chem. 2002, 2671–2681.
[5] a) R. C. Larock, E. K. Yum, J. Am. Chem. Soc. 1991, 113, 6689–6690;
b) R. C. Larock, E. K. Yum, M. D. Refvik, J. Org. Chem. 1998, 63, 7652–
7662; c) for a review, see: R. C. Larock, Top. Organomet. Chem. 2005, 14,
147–182.
General procedure for the low-catalyst-loading process
[6] J. Smidt, W. Hafner, R. Jira, J. Sedlmeier, R. Sieber, R. Rꢃttinger, H. Kojer,
Angew. Chem. 1959, 71, 176–182.
Stock solution of Pd(OAc)2 (10 or 20 mL) in DMSO (c=5 mm) was
added to
a
mixture of
1
(0.1 mmol),
2
(0.2 mmol), nBu4NI
[7] a) S. S. Stahl, Angew. Chem. 2004, 116, 3480–3501; Angew. Chem. Int. Ed.
2004, 43, 3400–3420; b) A. N. Campbell, S. S. Stahl, Acc. Chem. Res.
2012, 45, 851–863; c) W. Wu, H. Jiang, Acc. Chem. Res. 2012, 45, 1736–
1748; d) C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3464–
3484.
[8] a) R. A. Sheldon, I. W. C. E. Arends, G.-J. Ten Brink, A. Dijksman, Acc.
Chem. Res. 2002, 35, 774–781; b) M. Toyota, M. Ihara, Synlett 2002,
1211–1222; c) T. Nishimura, S. Uemura, Synlett 2004, 201–206; d) B. M.
Stoltz, Chem. Lett. 2004, 33, 362–367; e) M. S. Sigman, D. R. Jensen, Acc.
Chem. Res. 2006, 39, 221–229; f) Y. Deng, A. K. ꢆ. Persson, J.-E. Bꢀckvall,
Chem. Eur. J. 2012, 18, 11498–11523.
(1.0 equiv), and HOAc (1.0 equiv) in DMSO (1.0 mL) and the result-
ing mixture was stirred at 1500 rpm under an air atmosphere at
808C until TLC showed that the starting material 1 was completely
consumed. After quenching the reaction by the addition of ice
water, the reaction mixture was extracted by diethyl ether. The
combined organic extracts were washed with brine, dried over an-
hydrous Na2SO4, and concentrated in vacuo. The residue was sub-
mitted to 1H NMR spectroscopic analysis and purified by flash
column chromatography on silica gel.
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[9] a) D. R. Jensen, M. J. Schultz, J. A. Mueller, M. S. Sigman, Angew. Chem.
2003, 115, 3940–3943; Angew. Chem. Int. Ed. 2003, 42, 3810–3813;
b) C. N. Cornell, M. S. Sigman, Org. Lett. 2006, 8, 4117–4120; c) W.-P. To,
Y. Liu, T.-C. Lau, C.-M. Che, Chem. Eur. J. 2013, 19, 5654–5664; for palla-
dium(II)-catalyzed oxidative reactions (loading ꢀ1 mol%) in the pres-
ence of an oxidant other than dioxygen, see: d) C. T. Check, W. H. Hen-
derson, B. C. Wray, M. J. Vanden Eynden, J. P. Stambuli, J. Am. Chem. Soc.
2011, 133, 18503–18505; e) X. Jie, Y. Shang, P. Hu, W. Su, Angew. Chem.
2013, 125, 3718–3721; Angew. Chem. Int. Ed. 2013, 52, 3630–3633.
[10] a) R. C. Larock, T. R. Hightower, J. Org. Chem. 1993, 58, 5298–5300;
b) R. C. Larock, T. R. Hightower, G. A. Kraus, P. Hahn, D. Zheng, Tetrahe-
dron Lett. 1995, 36, 2423–2426.
J. H. M. Mommers, H. J. W. Henderickx, M. A. M. Walet, J. G. de Vries, Adv.
Synth. Catal. 2002, 344, 996–1002; d) J. G. de Vries, Dalton Trans. 2006,
421–429. For the X-ray structure of iodide-coordinated PdII complex
[Pd2I6]2À, see: e) J. Evans, L. O’Neill, V. L. Kambhampati, G. Rayner, S.
Turin, A. Genge, A. J. Dent, T. Neisius, J. Chem. Soc. Dalton Trans. 2002,
2207–2212.
[20] Halide effects in organic reactions: K. Fagnou, M. Lautens, Angew.
Chem. 2002, 114, 26–49; Angew. Chem. Int. Ed. 2002, 41, 26–47.
[21] a) Y. Chen, C.-H. Cho, R. C. Larock, Org. Lett. 2009, 11, 173–176; b) W.
Geng, W.-X. Zhang, W. Hao, Z. Xi, J. Am. Chem. Soc. 2012, 134, 20230–
20233; c) W. Hao, W. Geng, W.-X. Zhang, Z. Xi, Chem. Eur. J. 2014, 20,
2605–2612.
[11] a) R. A. T. M. van Benthem, H. Hiemstra, J. J. Michels, W. N. Speckamp, J.
Chem. Soc. Chem. Commun. 1994, 357–359; b) R. A. T. M. van Benthem,
H. Hiemstra, G. R. Longarela, W. N. Speckamp, Tetrahedron Lett. 1994, 35,
9281–9284.
[22] In our preliminary communication, the N-demethylation was proposed
to precede the reductive elimination step, see ref. [14b].
[23] At this catalyst concentration range, the kinetic data were collected
after the induction period.
[12] For detailed mechanistic studies, see: a) B. A. Steinhoff, S. R. Fix, S. S.
Stahl, J. Am. Chem. Soc. 2002, 124, 766–767; b) B. A. Steinhoff, S. S.
Stahl, J. Am. Chem. Soc. 2006, 128, 4348–4355.
[13] a) J.-E. Bꢀckvall, R. E. Nordberg, J. Am. Chem. Soc. 1981, 103, 4959–
4960; b) H. Grennberg, A. Gogoll, J.-E. Bꢀckvall, J. Org. Chem. 1991, 56,
5808–5811; c) C. M. R. Volla, J.-E. Bꢀckvall, Angew. Chem. 2013, 125,
14459–14463; Angew. Chem. Int. Ed. 2013, 52, 14209–14213, and refer-
ences cited therein.
[24] Solvent-stabilized nanoparticles are formed by simply heating Pd(OAc)2
in a polar solvent, see: a) M. T. Reetz, G. Lohmer, Chem. Commun. 1996,
1921–1922; b) M. T. Reetz, M. Maase, Adv. Mater. 1999, 11, 773–777.
[25] For selected examples on Pd/C-catalyzed oxidative reactions, see: a) S.
Rajappa, R. Sreenivasan, Tetrahedron 1980, 36, 3087–3090; b) S. T.
Gadge, M. V. Khedkar, S. R. Lanke, B. M. Bhanage, Adv. Synth. Catal.
2012, 354, 2049–2056; c) S. T. Gadge, B. M. Bhanage, J. Org. Chem.
2013, 78, 6793–6797.
[14] a) B. Yao, Q. Wang, J. Zhu, Angew. Chem. 2012, 124, 5260–5264; Angew.
Chem. Int. Ed. 2012, 51, 5170–5174; b) B. Yao, Q. Wang, J. Zhu, Angew.
Chem. 2012, 124, 12477–12481; Angew. Chem. Int. Ed. 2012, 51, 12311–
12315; c) B. Yao, Q. Wang, J. Zhu, Angew. Chem. 2013, 125, 13230–
13234; Angew. Chem. Int. Ed. 2013, 52, 12992–12996.
[15] For a review on metal-catalyzed coupling of two nucleophiles, see: C.
Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111, 1780–1724.
[16] For classification of domino reactions, see: L. F. Tietze, Chem. Rev. 1996,
96, 115–136.
[26] a) J. A. Widegren, R. G. Finke, J. Mol. Catal. A 2003, 198, 317–341;
b) R. H. Crabtree, Chem. Rev. 2012, 112, 1536–1554.
[27] N. T. S. Phan, M. Van Der Sluys, C. W. Jones, Adv. Synth. Catal. 2006, 348,
609–679.
[28] In general, PdII-catalyzed difunctionalization of alkenes proceeds
through a PdII/PdIV catalytic cycle. For reviews, see: a) A. Minatti, K.
Muniz, Chem. Soc. Rev. 2007, 36, 1142–1152; b) K. H. Jensen, M. S.
Sigman, Org. Biomol. Chem. 2008, 6, 4083–4088; c) R. I. McDonald, G.
Liu, S. S. Stahl, Chem. Rev. 2011, 111, 2981–3019; d) D. M. Schultz, J. P.
Wolfe, Synthesis 2012, 3, 351–361.
[29] Pd nanoparticles were observed in the Pd(OAc)2/DMSO/O2 system, see:
R. A. T. M. van Benthem, H. Hiemstra, P. W. N. M. van Leeuwen, J. W.
Geus, W. N. Speckamp, Angew. Chem. 1995, 107, 500–503; Angew.
Chem. Int. Ed. Engl. 1995, 34, 457–460.
[30] J. Stein, L. N. Lewis, Y. Gao, R. A. Scott, J. Am. Chem. Soc. 1999, 121,
3693–3703.
[31] a) H. Bçnnemann, W. Brijoux, R. Brinkmann, E. Dinjus, T. Joubem, B.
Korall, Angew. Chem. 1991, 103, 1344–1346; Angew. Chem. Int. Ed. Engl.
1991, 30, 1312–1314; b) M. T. Reetz, W. Helbig, J. Am. Chem. Soc. 1994,
116, 7401–7402.
[17] For other reactions involving s-indolylpalladium(II) complexes, see: a) A.
Yasuhara, Y. Takeda, N. Suzuki, T. Sakamoto, Chem. Pharm. Bull. 2002, 50,
235–238; b) X. Han, X. Lu, Org. Lett. 2010, 12, 3336–3339; c) C. C. Chen,
L.-Y. Chin, S.-C. Yang, M.-J. Wu, Org. Lett. 2010, 12, 5652–5655; d) R. ꢇl-
varez, C. Martꢄnez, Y. Madich, J. G. Denis, J. M. Aurrecoechea, ꢇ. R.
De Lera, Chem. Eur. J. 2010, 16, 12746–12753; e) X.-F. Xia, N. Wang, L.-L.
Zhang, X.-R. Song, X.-Y. Liu, Y.-M. Liang, J. Org. Chem. 2012, 77, 9163–
9170; f) Z. Hu, D. Liang, J. Zhao, J. Huang, Q. Zhu, Chem. Commun.
2012, 48, 7371–7373; g) G. Qiu, C. Chen, L. Yao, J. Wu, Adv. Synth. Catal.
2013, 355, 1579–1584; h) A. Arcadi, S. Cacchi, G. Fabrizi, A. Goggiamani,
A. Lazzetti, F. Marinelli, Org. Biomol. Chem. 2013, 11, 545–548; i) Z. Hu, J.
Wang, D. Liang, Q. Zhu, Adv. Synth. Catal. 2013, 355, 3290–3294; j) Q.
Wang, L. Huang, X. Wu, H. Jiang, Org. Lett. 2013, 15, 5940–5943; k) J.
Sheng, S. Li, J. Wu, Chem. Commun. 2014, 50, 578–580.
[32] By using aniline as reaction partner, only 3-unsubstituted indoles were
isolated.
[33] Retro-aminopalladation of alkenes has been proposed as a key elemen-
tary step in a PdII-catalyzed C2-alkylation of indoles, see: L. Jiao, E.
Herdtweck, T. Bach, J. Am. Chem. Soc. 2012, 134, 14563–14572.
[18] The pKa of ArNMe2H+: 5.2 in water, 2.5 in DMSO; the pKa of AcOH: 4.76
in water, 12.3 in DMSO.
[19] For halide-ligated Pd0 complexes, see: a) E. Negishi, T. Takahashi, K.
Akiyoshi, J. Chem. Soc. Chem. Commun. 1986, 1338–1339; b) C. Ama-
tore, M. Azzabi, A. Jutand, J. Am. Chem. Soc. 1991, 113, 8375–8384;
c) A. H. M. de Vries, F. J. Parlevliet, L. Schmieder-van de Vondervoort,
Received: May 20, 2014
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FULL PAPER
Low-loader: The title reaction was initi-
ated by aminopalladation of 1, followed
by ligand exchange of the resulting s-
indolylpalladium(II) complex with 2, re-
ductive elimination and N-demethyla-
tion (see scheme). Both the acetate and
iodide play important roles in channel-
ing the reaction in the desired direction.
The soluble iodide-ligated Pd0 species is
proposed to be the resting state of the
catalyst and its oxidation to the active
PdII species is the turnover-limiting step.
Conditions with a low loading of
&
Synthetic Methods
B. Yao, Q. Wang, J. Zhu*
&& – &&
Mechanistic Study on the
Palladium(II)-Catalyzed Synthesis of
2,3-Disubstituted Indoles Under
Aerobic Conditions: Anion Effects and
the Development of a Low-Catalyst-
Loading Process
Pd(OAc)2 (0.0005 to 0.001 equiv) were
subsequently developed.
&
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Chem. Eur. J. 2014, 20, 1 – 8
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!