Palladium-Catalyzed Regioselective Synthesis of 3-Arylindoles from N-Ts-Anilines and Styrenes

Article abstract of DOI:10.1002/anie.201702205

A Pd-catalyzed intermolecular oxidative annulation between N-Ts-anilines and styrenes was developed. This method offers a straightforward and robust approach to a wide range of 3-arylindoles using readily available starting materials with good functional-group tolerance and high regioselectivity and efficiency. Further elaboration of the products obtained from this process provided access to highly functionalized and structurally diverse indoles, for example, 3-(indol-3-yl)carbazoles, 1,9-dihydropyrrolo-[2,3-b]carbazoles, and 3′-aryl-3,5′-biindoles.

Full text of DOI:10.1002/anie.201702205

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Communications
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International Edition: DOI: 10.1002/anie.201702205
German Edition: DOI: 10.1002/ange.201702205
Homogeneous Catalysis
Palladium-Catalyzed Regioselective Synthesis of 3-Arylindoles from N-
Ts-Anilines and Styrenes
So Won Youn,* Tae Yun Ko, and Young Ho Jang
Abstract: A Pd-catalyzed intermolecular oxidative annulation
between N-Ts-anilines and styrenes was developed. This
method offers a straightforward and robust approach to
a wide range of 3-arylindoles using readily available starting
materials with good functional-group tolerance and high
regioselectivity and efficiency. Further elaboration of the
products obtained from this process provided access to
highly functionalized and structurally diverse indoles, for
example, 3-(indol-3-yl)carbazoles, 1,9-dihydropyrrolo-[2,3-
b]carbazoles, and 3’-aryl-3,5’-biindoles.
A
s a result of the various interesting biological properties of
3-arylindoles (Figure 1),[1] a diverse range of synthetic meth-
ods for their construction have been developed, and more
efficient and regioselective synthetic strategies continue to be
pursued.
In general, 3-arylindoles have been formed by transition-
À
metal-catalyzed intramolecular cyclization through either C
[2]
À
C or C N bond formation or direct C3-arylation of
indoles.[3] Despite significant advancements, achieving regio-
selectivity represents a major challenge in the latter, whereas
the former requires several steps or limited commercially
available reagents for preparation of the starting materials.
Recently, metal-catalyzed couplings of aryl hydroxylamines,
nitroarenes, or nitrosoarenes with alkynes have been also
developed.[4]
Figure 1. Bioactive 3-arylindoles.
The ideal indole scaffold synthesis would be a reaction
between two simple and readily available starting materials,
À
À
for example, anilines and alkenes, with both a C C and C N
bond formation. The Maiti group reported excellent work on
the Pd-catalyzed decarboxylative coupling of diarylamines
with cinnamic acids for the synthesis of 3-arylindoles (Scheme
1a).[5] However, regioselective synthesis from simple anilines
and styrenes remains an attractive but challenging task.
Indeed, the Maiti[6a] and Jana[6b] groups independently
reported a Pd-catalyzed dehydrogenative coupling of anilines
with styrenes to afford 2-arylindoles (Scheme 1b,c).
Given the low cost, diversity, and wide availability of
anilines and styrenes, we were interested in developing a new
catalytic method using these simple substrates for the facile
and regioselective formation of 3-arylindoles. Inspired by
[*] Prof. Dr. S. W. Youn, T. Y. Ko, Y. H. Jang
Center for New Directions in Organic Synthesis
Department of Chemistry and Institute for Material Design
Hanyang University, Seoul 04763 (Korea)
E-mail: sowony73@hanyang.ac.kr
Scheme 1. Regioselective synthesis of 2- or 3-arylindoles from anilines
and alkenes.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201702205.
reports on various Pd-catalyzed reactions involving ortho-
palladation of the anilines,[5–7] an influence of N-protecting
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Table 2: Substrate scope.[a]
groups (PGs) on the reactivity,[8,9] and a marked dependence
of the regioselectivity on the ligands,[10] we reasoned that this
challenging task could be accomplished through a carefully
chosen catalytic system consisting of the right combination of
reaction parameters (e.g., Pd catalyst, oxidant, ligand) and N-
PGs.
As part of our continued interest in indole synthesis,[2e,9]
À
À
we herein report a Pd-catalyzed one-pot C C/C N bond
formation sequence between anilines and styrenes for the
convenient synthesis of 3-arylindoles, which proceeds with
high efficiency and regioselectivity (Scheme 1d). In sharp
contrast to the opposite regioselectivity pattern of the
previous methods (Scheme 1b,c),[6] this new method offers
straightforward access to the synthetically valuable 3-arylin-
doles, which were previously inaccessible from styrenes and
anilines.
In light of our recent success in the synthesis of various N-
heterocycles using N-Ts-aniline derivatives,[2e,8d,9] we began
our studies on the proposed reaction using 1a and styrene as
the substrates. After scrupulous examination of the reaction
parameters, we found that a reagent mix consisting of
Pd(OAc)2, Cu(OAc)2, and a bidentate nitrogen ligand in
toluene afforded the desired product 2a as a major isomer,
along with a small amount of 3a.[11] As expected, a substantial
ligand effect was observed in this transformation. Among the
various bidentate nitrogen ligands examined, 4,7-disubsti-
tuted-1,10-phenanthroline derivatives proved to be superior
to the others, with BPhen giving the best results (59%, 2a/
3a = 6:1, Table 1a). Control experiments indicated that all
the reaction components (Pd catalyst, oxidant, ligand) were
essential for the reaction to occur.
[a] Yields of isolated product and the ratios of the two isomers (2/3).
[b] Using 1.0 g of 1a. [c] Using 10 mol% Pd(OAc)2, 20 mol% BPhen, and
4 equiv 4-nitrostyrene. [d] With another 1.5 equiv of olefin added after
12 h.
Table 1: Optimization studies.
Further optimization of the reaction conditions
showed that the use of Cu(OAc)2·H2O in air was
more effective (71%, 2a/3a = 8:1) than that of
Cu(OAc)2 under argon atmosphere, and some qui-
none-based additives strongly influenced the reac-
tion (Table 1b). The regioselectivity was observed to
depend on the substitution pattern of the quinones.
Among various quinones examined, BQ was identi-
fied as an optimal additive (81%, 2a/3a = 10:1). BQ
has been well documented to function as a ligand of
Pd and to positively influence various Pd-catalyzed
reactions.[12] On the basis of our experimental find-
ings, including the observation that BQ is ineffective
as an oxidant, BQ appears to serve as a coligand in
this transformation. Subsequently, we examined the
effect of differnt N-PGs (Table 1c). A sulfonyl
group, especially Ts, was revealed as the optimal
protecting group. Overall, the combination of all the
reaction components, especially BPhen and BQ as
ligands, and the N-Ts group on the aniline, appears to
be critical for achieving high efficiency and regiose-
lectivity.
Having established a viable catalytic system, we
All reactions were performed in a reaction block under aerobic conditions (open to
air in an uncapped vial) and yields of isolated product are given unless otherwise
noted. NR: No reaction occurred. [a] At 1408C in a closed vial. [b] 1H NMR yield.
[c] Performed in an oil bath. [d] Without BQ.
set out to explore the scope of this process. A wide
range of styrenes underwent the reaction smoothly
to afford the corresponding 3-arylindoles (2) in
2
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moderate to good yields with high regioselectiv-
ity, irrespective of their electronic properties and
the positions of their substituents (Table 2a).
Both electron-donating and electron-withdraw-
ing substituents at the para position of the
anilines were well tolerated (2p–t, Table 2b).
Anilines with an alkoxy substituent at the meta
position provided single regioisomeric indoles
2u–v through reaction at the sterically less
À
encumbered aryl C H bond, whereas the reac-
tion of 2-naphthylamine resulted in a mixture of
two regioisomers (2w/2w’). Furthermore, N,N’-
bistosyl-1,3-diaminobenzene afforded the fused
tricyclic 1,7-dihydropyrrolo[3,2-f]indole 2y in
a synthetically useful yield and perfect regiose-
lectivity. By contrast, the steric properties of the
anilines strongly influenced the reaction, and
reaction of ortho-substituted anilines failed to
afford the desired products. We also investigated
the reaction of 1a with alkyl-substituted alkenes.
Secondary alkyl-substituted alkenes proved to be
suitable substrates for the regioselective forma-
tion of 3-alkylindoles and gave good yields (2z–
aa, Table 2c). By contrast, primary alkyl deriv-
atives (e.g., 1-octene) led to a complicated mix-
ture. We note that the ratios of 3-arylindoles (2)
to 2-arylindoles (3) were generally excellent, and
various functional groups were well tolerated.
Moreover, the reaction on a gram scale gave
a comparable yield (2n, 70%), thus showing the
synthetic potential of this method.
To highlight the synthetic utility of this
transformation, we carried out some derivatiza-
tions of the indole products. Smooth removal of
the N-Ts group led to NH-free indoles 4a–c in
Scheme 2. Synthetic application.
high yields (Scheme 2a). Notably, the separation of 3- and 2-
aryl regioisomeric mixtures of NH-free indoles is generally
very easy, giving pure 3-arylindole products only. Further
elaboration of 2k and 2s, which have a bromo substituent at
either the indole moiety or the 3-aryl substituent, proceeded
smoothly to give the highly conjugated, polysubstituted
indoles in high yields (Scheme 2b). Given these successful
Suzuki reactions, we envisioned the installation of the
carbazole skeleton on molecular templates utilizing the
synthetic method developed by our group.[9g] As illustrated
in Scheme 2c, Suzuki reaction followed by Pd-catalyzed
fore, the four potential intermediates (I,II and I’,II’) were
independently synthesized and subjected to the standard
conditions (Scheme 3a). Reaction of I led to the formation of
2a in a high yield after a very short reaction time (1 h, 98%),
whereas the conversion of I’ into 3a was rather slow (24 h),
À
intramolecular oxidative C H amidation were readily ac-
complished to afford the 3-(indol-3-yl)carbazole 4j and fused
tetracyclic 1,9-dihydropyrrolo[2,3-b]carbazole 4l in regioiso-
merically pure form. In addition, the iterative process
successfully proceeded to give 3’-aryl-3,5’-biindole 4n in
67% yield with excellent regioselectivity (Scheme 2d).
To gain mechanistic insight into this reaction, a series of
control experiments were performed.[11] Two mechanistic
À
modes were conceived for this process: 1) C C bond
À
formation through ortho-palladation, followed by C N bond
formation through cyclization[6] or 2) C N bond formation
À
through an intermolecular aza-Wacker-type reaction,[13] fol-
À
lowed by C C bond formation through cyclization. There-
Scheme 3. Mechanistic studies.
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albeit with a good yield (71%). In sharp contrast, no reaction
occurred with II or II’. Furthermore, I’-type intermediates
could be isolated in 5–10% yields along with the desired
indole products 2/3 after 12 h, whereas I-type intermediates
were not observed (as monitored by TLC and 1H NMR),
presumably because of their rapid and effective cyclization.
Another putative intermediate would be indolines, which can
easily be oxidized to the corresponding indoles.[6a] However,
no conversion of III or III’ under the standard conditions was
observed. All these results suggest that this reaction proceeds
through the first pathway, operating through the intermediacy
of a discrete Fujiwara–Moritani reaction, followed by intra-
molecular aza-Wacker-type cyclization. In addition, these
findings suggest the formation of I/I’ as the rate- and
regioselectivity-determining step.
arylindole 2. In parallel, the so-obtained Pd0 is reoxidized to
the catalytically active PdII species by Cu(OAc)2·H2O and O2
in air to complete the catalytic cycle.
In summary, we have developed a new Pd-catalyzed
intermolecular oxidative annulation between N-Ts-anilines
and styrenes. This new method represents an attractive and
potentially powerful route for straightforward access to
a diverse range of 3-arylindoles, a privileged motif found in
numerous bioactive compounds. Further elaboration of the
resulting products provides access to highly functionalized
and structurally diverse indoles.
Acknowledgements
Competition experiments with deuterium-labelled 1a or
styrene (Scheme 3b) and the observation of no D/H exchange
in the substrate or product[11] suggest that the rate-determin-
This work was supported by both Basic Science Research
Program and Nano·Material Technology Department Pro-
gram through the National Research Foundation of Korea
(NRF) funded by the Korea government (MSIP) (Nos.
2012M3A7B4049644, 2015R1A2A2A01002559, and 2014-
011165).
À
ing step may not involve irreversible C H cleavage and b-H
elimination.[14]
Next, we performed competition experiments with
a series of 4-substituted N-Ts-anilines and styrenes (Scheme
3c). The electron-neutral and electron-deficient aniline sub-
strates reacted considerably faster than their electron-rich
counterparts, whereas more electron-rich styrenes reacted
preferentially.
Conflict of interest
The authors declare no conflict of interest.
On the basis of our experimental findings, we proposed
a plausible mechanism (Scheme 4). Having uncovered the
importance of both the presence and the acidity of the NH
À
Keywords: C H activation · homogeneous catalysis · indoles ·
palladium · regioselectivity
moiety,[11] we speculated that an initial Pd N bond formation
À
occurs, thereby generating the PdII species A/A’, which
À
undergoes an irreversible sulfonamide-directed ortho-C H
bond activation through a concerted metalation-deprotona-
tion (CMD) pathway to give six-membered intermediate B.
While the determining factors for regioselectivity remained to
be clarified, the coordination (C) and carbopalladation (D) of
styrene, which are the regioselectivity-determining steps,
followed by b-H elimination completes the Fujiwara–Mor-
itani process, resulting in preferential formation of the
branched alkenylation intermediate E. Subsequently, intra-
molecular aza-Wacker-type cyclization of E, involving amino-
palladation (F) followed by b-H elimination, provides 3-
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Scheme 4. Proposed mechanism.
4
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Manuscript received: March 2, 2017
Revised: March 27, 2017
Final Article published: && &&, &&&&
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Homogeneous Catalysis
S. W. Youn,* T. Y. Ko,
Y. H. Jang
&&&& — &&&&
Palladium-Catalyzed Regioselective
Synthesis of 3-Arylindoles from N-Ts-
Anilines and Styrenes
Hello from the other side: A Pd-catalyzed
intermolecular oxidative annulation for
ods, this method offers facile access to
the synthetically valuable 3-arylindoles,
which were previously inaccessible from
styrenes and anilines, with high efficiency
and excellent regioselectivity.
À
À
one-pot C C/C N bond formation was
developed. In contrast to the opposite
regioselectivity pattern of related meth-
6
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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