PtCl4-catalyzed cyclization of N-acetyl-2-alkynylanilines: A mild and efficient synthesis of N-acetyl-2-substituted indoles

Article abstract of DOI:10.1016/j.tetlet.2018.01.014

An efficient synthesis of N-acetyl-2-substituted indole derivatives via direct intramolecular hydroamination of N-acetyl-2-alkynylaniline derivatives was developed. The reaction could be applied to a wide range of substrates employing only 1–2 mol% of PtCl₄ as the catalyst to furnish the desired indole products in moderate to excellent yields. The current protocol is efficient, reliable and scalable, and could serve as an important tool for convenient and rapid access to this important class of N-heterocyclic skeleton from readily available substrates.

Full text of DOI:10.1016/j.tetlet.2018.01.014

Accepted Manuscript
PtCl4-Catalyzed cyclization of N-acetyl-2-alkynylanilines: a mild and efficient
synthesis of N-acetyl-2-substituted indoles
Nattawadee Chaisan, Wilailak Kaewsri, Charnsak Thongsornkleeb, Jumreang
Tummatorn, Somsak Ruchirawat
PII:
S0040-4039(18)30026-1
https://doi.org/10.1016/j.tetlet.2018.01.014
TETL 49601
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
15 November 2017
25 December 2017
5 January 2018
Please cite this article as: Chaisan, N., Kaewsri, W., Thongsornkleeb, C., Tummatorn, J., Ruchirawat, S., PtCl4-
Catalyzed cyclization of N-acetyl-2-alkynylanilines: a mild and efficient synthesis of N-acetyl-2-substituted indoles,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.01.014
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PtCl4-Catalyzed cyclization of N-acetyl-2-
alkynylanilines: a mild and efficient synthesis of
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N-acetyl-2-substituted indoles
Nattawadee Chaisan, Wilailak Kaewsri, Charnsak Thongsornkleeb, Jumreang Tummatorn, Somsak Ruchirawat
R2
R5
R2
R1
R3
R4
R3
R4
1-2 mol% PtCl4
R1
DCM, rt
or
DCE, reflux
N
Ac
NHAc
R5
23 examples
56% to quantitative yields
amenable to gram-scale synthesis

1
Tetrahedron Letters
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PtCl4-Catalyzed cyclization of N-acetyl-2-alkynylanilines: a mild and efficient
synthesis of N-acetyl-2-substituted indoles
Nattawadee Chaisan,a Wilailak Kaewsri,a Charnsak Thongsornkleeb,a,b,* Jumreang Tummatorn,a,c and
Somsak Ruchirawata,c
a
Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Education,
54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand.
b
Laboratory of Organic Synthesis, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand.
c Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand.
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient synthesis of N-acetyl-2-substituted indole derivatives via direct intramolecular
hydroamination of N-acetyl-2-alkynylaniline derivatives was developed. The reaction could be
applied to a wide range of substrates employing only 1-2 mol% of PtCl4 as the catalyst to furnish
the desired indole products in moderate to excellent yields. The current protocol is efficient,
reliable and scalable, and could serve as an important tool for convenient and rapid access to this
important class of N-heterocyclic skeleton from readily available substrates.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Indoles
2-Alkynylanilines
Catalysis
Hydroamination
Cyclization
O
Introduction
OH
Me
NMe2
MeO
HO
It would be very difficult to overemphasize the importance of
indoles in compounds of biological, pharmacological and
medicinal significance. The realm of natural products, marketed
drugs and compounds in clinical trials is filled with molecules
containing indole nucleus in their structures as exemplified in
Figure 1.1 In fact, indole can be referred as a privileged structure
of significant medicinal values. As a result, many chemists are
still actively investigating strategies and methods for efficient
generation of this essential nucleus as evidenced in the literature.2
N
N
H
O
Cl
Bufotenine
Anti-psychotic agent
Indomethacin
Anti-inflammatory drug
OMe
MsHN
O
N
Me
N
N
H
Several strategies and methods for the preparation of indole
derivatives have been described starting from a variety of
substrates.2b,c One of the most common and reliable strategies
focuses on the direct intramolecular hydroamination of 2-
alkynylaniline derivatives employing bases,3a,b electrochemical
method,3c and a wide variety of transition metal catalysts.4 In
addition, 2-alkynylaniline derivatives have also been employed in
tandem intramolecular cyclization-functionalization to provide
indole scaffold with the incorporation of different functional
handles.5 For the method employing transition metal catalysts,
the most prevalent catalysts utilized were based on palladium,4a,b
indium4e and gold complexes.4d,f,h However, some of the reactions
carried out using these catalysts suffer from high catalyst loading
(5-10 mol%), high reaction temperatures (50-110 °C), and/or
long reaction time (up to 24 h in some systems).4 In addition,
most of these methods seemed to work well only with the 2-
alkynylaniline substrates containing free amino group (-NH2)
NH
HN
N
Delavirdine
Anti-HIV drug
N
Me
Obatoclax
Phase II clinical trials for
several types of cancers
HN
H
N
O
O
OEt
S
HO
Br
NHMe
N
N
F
H
Me
AG-14699
Phase II clinical trials for
ovarian cancer
Arbidol
Antiviral drug
Figure 1. Examples of natural products, marketed drugs and
compounds in clinical trials containing indole scaffolds.

2
Tetrahedron Letters
while there were only few published methods of N-protected 2-
the same conversion in refluxing acetonitrile,4b while PtCl4 in our
reaction seemed to be shut down in acetonitrile. From these
results, it was sufficient to conclude that DCM was the solvent of
choice for this transformation. In lowering the amount of PtCl4
catalyst even further, it was found that 2 mol% of the catalyst
could fully convert compound 1a to the corresponding indole 2a
in excellent yield upon stirring at room temperature in DCM
overnight (entry 8). A comparable yield (97%, entry 9) of
product 2a was obtained when the reaction was conducted with 1
mol% of PtCl4. Finally, the reaction with the catalyst loading as
low as 0.5 mol% was attempted (entry 10). Under these
conditions, the reaction became significantly more sluggish and
even after allowing the reaction to stir at room temperature
overnight, only 8% yield of the desired indole product was
obtained with the recovery of all remaining starting material. We
suspected that at such extremely low catalyst loading, the
reaction required much longer time to initiate and proceed. From
these results, it was clear that PtCl4 was superior to other
platinum complexes for the cyclization of alkynylaniline 1a to
indole 2a with excellent reaction efficiency at a very low loading
of 1-2 mol% under mild conditions, in DCM at room temperature
overnight.
alkynylaniline substrates undergoing the cyclization. For
examples, PdCl2(CH3CN)2 (13 mol%) in refluxing acetonitrile4b
and InBr3 (5 mol%) in refluxing toluene4e were utilized in the
cyclization of N-acetyl-2-alkynyl anilines to provide the
corresponding N-acetyl indole products in relatively moderate
yields of 69% and 71%, respectively (Scheme 1). To expand the
repertoire of methods available in the synthetic toolbox for the
construction of this very important class of heterocyclic skeleton,
we wish to report PtCl4 as a mild and very efficient catalyst for
the conversion of N-acetyl-2-alkynylanilines to N-acetyl-2-
substituted indoles. The current procedure is highlighted by low
catalyst loading, low reaction temperature, and applicability to a
wide range of substrates.
Scheme 1. Methods for the construction of indole derivatives via
hydroamination of 2-alkynylanilines.
Results and discussion
With the optimal conditions in hands, the scope of the
cyclization of 2-alkynylanilines 1 to indole derivatives 2 was
next studied. The results of our study are shown in Table 2. For
substrate 1a, the reaction proceeded at room temperature to give
the desired product 2a in excellent yield (99%). When substrate
1a-Bz (containing N-Bz) was employed, the reaction also
proceeded excellently at ambient temperature to give the
corresponding indole 2a-Bz in 98% yield A sulfonamide
substrate was next investigated with substrate 1a-Ts, the reaction
of which proceeded smoothly at room temperature to give the
desired product 2a-Ts in 98%. We next tested our conditions
with N-Boc protected substrate (1a-Boc) which was found to be
well susceptible under our conditions and provided the
corresponding product 2a-Boc in 98% yield. However, for
substrate with free NH2 group, the reaction was more sluggish at
room temperature. In this case, the reaction was conducted in
refluxing DCE instead and it underwent a very clean conversion
to give the corresponding N-unprotected indole 2a-H in 84%
isolated yield.
To commence the investigation, substrate 1a was constructed6
and employed in the optimization study. We subjected compound
1a to conditions as summarized in Table 1. We focused on
screening the reaction with platinum catalysts for the cyclization
of substrate 1a. As summarized in Table 1, when 10 mol% of
K2PtCl6 was utilized in DCM, the conversion of alkynylaniline
1a to the corresponding indole 2a was effected in 86% yield after
stirring the reaction mixture at room temperature overnight (entry
1). PtCl2 was next investigated; at 10 mol% in DCM at room
temperature overnight, compound 1a was smoothly converted to
indole 2a with excellent efficiency (98%, entry 2). However, in
an attempt to lower the catalyst loading to 2 mol% of PtCl2,
product 2a was obtained in only 37% yield (entry 3). PtCl4 was
next investigated, first at 10 mol%. At this amount, the reaction
was complete within 3 h and the desired product was obtained in
96% yield (entry 4). When the amount of PtCl4 was lowered to 5
mol%, the reaction took longer to complete (5 h), however, the
desired product 2a was obtained with comparable efficiency
(99%, entry 5). In an attempt to study the effect of different
solvents, the cyclization was conducted with 5 mol% of PtCl4 in
acetonitrile and DMF at room temperature for 4h and 3h,
respectively, to find that the reactions produced no product, but
only recovered starting material 1a (entries 6-7). This result was
in a stark contrast to the previous report that PdCl2 could effect
The effects of R1 group were next studied (R2-R5 = H). For
substrate 1b (R1 = para-methoxyphenyl), the reaction again
proceeded uneventfully to give the desired indole 2b in
quantitative yield. Next, the substrates with R1
= para-
fluorophenyl and para-chlorophenyl groups were attempted. The
reactions were very clean and could afford the desired indoles 2c
Table 1. Optimization of cyclization of compound 1a to indole 2a.
Entry
Catalyst
K2PtCl6
PtCl2
PtCl2
PtCl4
PtCl4
PtCl4
PtCl4
PtCl4
PtCl4
PtCl4
Equiv
10 mol%
10 mol%
2 mol%
10 mol%
5 mol%
5 mol%
5 mol%
2 mol%
1 mol%
0.5 mol%
Solvent
DCM
DCM
DCM
DCM
DCM
CH3CN
DMF
Temp
rt
Time
overnight
overnight
overnight
3 h
Yielda
86%
98%
37%
96%
99%
NR
1
2
rt
3
rt
4
rt
5
rt
5 h
6
rt
4 h
7
rt
3 h
NR
8
DCM
DCM
DCM
rt
rt
overnight
overnight
overnight
99%
97%
8%
9
10
rt
aIsolated yields.

3
Table 2. Scope of the PtCl4-catalyzed cyclization of 2-alkynylanilines 1 to indoles 2.a
aIsolated yields. bReactions were conducted in refluxing DCE and monitored by TLC.
and 2d in almost quantitative yields (97% and 98%,
respectively). Substrates with R1 = alkyl groups were next
investigated. As shown in Table 2, substrates 1e (R1 = n-Bu), 1f
(R1 = t-Bu), and 1g (R1 = cyclohexyl) smoothly underwent the
cyclization to produce the desired indoles 2e-2g in excellent
yields (96%, 83%, and 96%, respectively), although the yield of
2f (R1 = t-Bu) was slightly lower possibly due to the bulkiness of
the t-Bu group. However, this result was still a vast improvement
over the previously reported procedure of a similar substrate.4e
yielded in 72%. We also examined substrates substituted with
halogen atoms. For substrate 1k with fluorine atom at R4, the
reaction was more sluggish in DCM at room temperature and
required heating at reflux in DCE. Under these conditions,
product 2k was cleanly produced in close to quantitative yield
(98%). Next, the substrates containing chlorine atoms at various
positions were examined. For 1l with R2 = Cl, the reaction could
proceed smoothly in DCM at room temperature to produce
product 2l in 94% yield. The similar result was also obtained
with substrate 1m with R3 = Cl; the reaction also easily occurred
at room temperature to give the desired indole 2m in quantitative
yield. For substrate 1n with chlorine atom at R4 position, the
reaction required heating at reflux in DCE to proceed to
completion to give indole 2n in quantitative yield. It should be
noted that the conditions required for substrate 1n to proceed in
this case was identical to substrate 1k with fluorine atom also at
R4 position. For substrate 1o with R5 = Cl, the reaction readily
proceeded in DCM at room temperature to afford indole 2o in
97% yield. We next examined substrate containing bromine atom
at R3 position (1p) to find that it could also be converted readily
to the corresponding indole 2p in quantitative yield at room
temperature. The result of compound 1p (R3 = Br) corroborated
Substrate 1h (R1
= 1-cyclohexenyl) was also attempted.
However, the reaction of this substrate was less efficient, giving
the desired product in only 65% yield. It was speculated that the
double bond in the cyclohexenyl group may have interfered with
the coordination of PtCl4 on the alkyne as alkene could also
coordinate to PtCl4.7
Next, the effects of R2-R5 substituents were examined while
keeping R1 as phenyl group. 2-Alkynylaniline 1i, substituted with
electronically neutral methyl group at R3, was subjected to the
standard conditions. In this case, the reaction provided the
desired indole 2i in excellent yield (99%). However, when the
substrate containing electron-donating OMe groups at R3 and R4
(1j) was attempted, the reaction was less efficient; product 2j was

4
Tetrahedron
well with that of compound 1m (R3 = Cl). Among the substrates
conditions using 2 mol% of PtCl4, after stirring at room
temperature for 70 h, the reaction cleanly afforded indole 2a in
99% yield (1.074 g, 4.56 mmol). Although requiring longer
reaction time for a gram-scale synthesis, the reaction still
proceeded with excellent efficiency.
containing halogen atoms, the position of these halogen atoms
seemed to dictate the reactivity of the substrates. They were more
reactive with halogen atoms occupying positions R2, R3, and R5
in the substrates (1l, 1m, 1o, and 1p), the reactions of which
readily proceeded in DCM at room temperature. However, when
the halogen atoms occupied position R4 in the substrates, which
is para to the alkynyl bond (1k and 1n), the reactivity of these
compounds seemed to drop; heating the reactions in refluxing
DCE became necessary to reach complete conversions.
Nevertheless, all reactions of compounds containing halogen
atoms occurred with excellent efficiencies.
2 mol% PtCl4
DCM, rt
N
Ac
NHAc
70 h
1a
2a 99%
(1.074 g, 4.56 mmol)
,
(1.084 g, 4.61 mmol)
For the substrates containing strongly electron-withdrawing
substituents on the aniline ring at R3, as in substrates 1q (R3 =
CO2Me), 1r (R3 = CN), and 1s (R3 = NO2), all three reactions
required refluxing in DCE to achieve the desired conversions.
The efficiencies of these reactions became lower when compared
to those substrates containing halogen atoms (vide supra). For
substrate 1q, the reaction provided the corresponding product
(2q) in 88% yield while substrates 1r and 1s were less efficiently
converted to the products, both giving the corresponding indoles
2r and 2s in 56% yields. In comparing the reactivity of substrates
1q-1s to substrates 1m (R3 = Cl) and 1p (R3 = Br) where these
substituents were all located at the para-position to the amine
group, it was clear that the inductive effect of the halogen atoms
did not affect the nucleophilicity of the amine group to
participate in the hydroamination reaction as much as that of the
more strongly electron-withdrawing groups. The inductive effect
of halogen atoms was more noticeable when they were at the R4
position (para to the alkynyl group) as evidenced in the reactions
of substrates 1k (R4 = F) and 1n (R4 = Cl), both of which
required heating at reflux in DCE to achieve full conversions.
Scheme 2. Gram-scale preparation of indole 2a.
The catalytic cycle of the current PtCl4-catalyzed
hydroamination of N-acetyl-2-alkynylanilines (1) was proposed
as shown in Scheme 3. The reaction started when PtCl4
coordinated with and activated the triple bond of substrate 1
which would lead to intermediate A with nascent partial positive
character of the carbon atom next to R1 group which may be
stabilized by R1. The lone pair electrons on the ortho-nitrogen
atom then added to the electrophilically activated triple bond.
Upon a loss of HCl, intermediate B was generated. Proto-
deplatination of intermediate B ensued to give the corresponding
indole product 2 along with the re-generation of PtCl4 to
participate in the next catalytic cycle.9 In hindsight, for the
cyclization reactions of substrates 1v (R1 = TMS) and 1w (R1 =
H) (Table 2), we speculated that upon activation by PtCl4 the
partial positive character of the alkynyl carbon (intermediate A)
could not be sufficiently stabilized, and therefore the reactions
could not proceed further and only starting materials were
recovered (vide supra).
We also attempted the reactions with substrates 1t with R1 =
CH2OH and found that the reaction was not successful even with
heating in refluxing DCE. The reaction only yielded
decomposition with a small amount of the substrate was
recovered. A similar result was also observed in the substrate
with R1 = CH2OAc (1u) where it also decomposed under heating
in refluxing DCE. These results were not unexpected as allylic
and propargylic systems substituted with hydroxyl and acetate
groups are known to participate in a variety of transition metal-
catalyzed reactions.8 When we attempted the reactions with
substrates 1v (R1 = TMS) and 1w (R1 = H), we found that there
was no reaction in both cases and starting materials were
recovered.
Conclusions
In conclusion, we have developed a mild and very efficient
PtCl4-catalyzed hydroamination of 2-alkynylaniline derivatives
for the convenient preparation of 2-substituted indoles. The
procedure was applicable to a wide range of substrates and
required very low catalyst loading of 1-2 mol%. Most substrates
were cleanly converted to the desired 2-substituted indole
products in DCM at room temperature in good to excellent
yields, while in some substrates, especially those containing
halogen atoms at certain positions and strongly electron-
withdrawing substituents, required refluxing DCE conditions to
still afford the desired indole products in moderate to excellent
yields. The current procedure is very convenient and scalable for
gram-scale preparation of indoles, as well as applicable to a wide
variety of substrates, thus it would serve as a valuable synthetic
tool to organic chemists for the construction of this important N-
heterocyclic scaffold.
In addition to applicability of the procedure to wide scope of
substrates, the current conditions could be amenable to gram-
scale preparation of indoles. As illustrated in Scheme 2, when
substrate 1a (1.084 g, 4.61 mmol) was subjected to the optimal
Scheme 3. Proposed mechanism of PtCl4-catalyzed hydroamination of N-acetyl-2-alkynylanilines.

5
Molecules 2013, 18, 6620–6662. (f) Sonsona, I. G. Synlett 2015,
Experimental section
26, 2325–2326. (g) El Sayed, M. T.; Hamdy, N. A.; Osman, D. A.;
Ahmed, K. M. Adv. Mod. Oncol. Res. 2015, 1, 20–35. (h)
Sravanthi, T. V.; Manju, S. L. Eur. J. Pharm. Sci. 2016, 91, 1–10.
General procedure for PtCl4-catalyzed intramolecular
hydroamination of N-acetyl-2-alkynylaniline substrates for the
synthesis of N-acetyl-2-substituted indole derivatives (Procedure
A): A solution of N-acetyl-2-phenylethynyllaniline (1a) (60.1
mg, 0.2554 mmol, 1.00 equiv) in DCM (5.0 mL) was added with
PtCl4 (1.6 mg, 0.0060 mmol, 0.02 equiv) in one portion. The
resulting reaction mixture was allowed to stir at room
temperature until the reaction was complete as monitored by
TLC. Upon completion, the reaction mixture was filtered through
a short plug of silica gel while rinsing with DCM to remove the
catalyst. The filtrate solution was concentrated under reduced
pressure to give 59.4 mg (99 %) of analytically pure indole 2a.
2. (a) Gribble, G. W. In Indole Ring Synthesis: From Natural
Products to Drug Discovery; John Wiley & Sons: West Sussex,
UK, 2016. (b) Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011,
67, 7195–7210. (c) Vicente, R. Org. Biomol. Chem. 2011, 9,
6469–6480.
3. (a) Yasuhara, A.; Kanamori, Y.; Kaneko, M.; Numata, A.; Kondo
Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 529–534.
(b) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.;
Knochel, P. Tetrahedron 2003, 59 1571–1587. (c) Arcadi, A.;
Bianchi, G.; Inesi, A.; Marinelli, F.; Rossi, L. Eur. J. Org. Chem.
2008, 783–787.
4. (a) Utimoto, K.; Miwa, H.; Nozaki, H. Tetrahedron Lett. 1981, 22,
4277–4278. (b) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989,
54, 5856–5866. (c) Sakai, N.; Annaka, K.; Konakahara, T. Org.
Lett. 2004, 6, 1527–1530. (d) Ambrogio, I.; Arcadi, A.; Cacchi, S.;
Fabrizi, G.; Marinelli, F. Synlett. 2007, 1775–1779. (e) Sakai, N.;
Annaka, K.; Fujita, A.; Sato, A.; Konakahara, T. J. Org. Chem.
2008, 73, 4160–4165. (f) Majumdar, K. C.; Samanta, S.;
Chattopadhyay, B. Tetrahedron Lett. 2008, 49, 7213–7216. (g)
Kumaran, E.; Leong, W. K. Tetrahedron Lett. 2014, 55, 5495–
5498. (h) Liang, S.; Hammond, L.; Xu, B.; Hammond, G. B. Adv.
Synth. Catal. 2016, 358, 3313–3318.
General procedure for PtCl4-catalyzed intramolecular
hydroamination of N-acetyl-2-alkynylaniline substrates for the
synthesis of N-acetyl-2-substituted indole derivatives (Procedure
B): A solution of N-(5-fluoro-2-(phenylethynyl)phenyl)acetamide
(1k) (52.8 mg, 0.2085 mmol, 1.00 equiv) in DCE (5.0 mL) was
added with PtCl4 (1.2 mg, 0.0045 mmol, 0.02 equiv) in one
portion. The resulting reaction mixture was equipped with a
condenser and heated at reflux until the reaction was complete as
monitored by TLC. Upon completion, the reaction mixture was
filtered through a short plug of silica gel while rinsing with DCM
to remove the catalyst. The filtrate solution was concentrated
under reduced pressure to give 51.7 mg (98 %) of analytically
pure indole 2k.
5. (a) Cacchi, S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63, 1001–
1011. (b) Barluenga, J.; Trincado, M.; Rubio, E.; González, J. M.
Angew. Chem. Int. Ed. 2003, 42, 2406 – 2409. (c) Tang, S.; Xie,
Y.-X.; Li, J.-H.; Wang, N.-X. Synthesis 2007, 1841–1847. (d)
Praveen, C.; Karthikeyan, K.; Perumal, P. T. Tetrahedron 2009,
65, 9244–9255. (e) Xu, C.; Murugan, V. K.; Pullarkat, S. A. Org.
Biomol. Chem. 2012, 10, 3875–3881. (f) Janreddy, D.; Kavala, V.;
Kuo, C.-W.; Kuo, T.-S.; He, C.-H.; Yao, C.-F. Tetrahedron 2013,
69, 3323–3330. (g) Liu, J.; Xie, X.; Liu, Y. Chem. Commun. 2013,
49, 11794–11796. (h) Feng, X.; Wang, H.; Yang, B.; Fan, R. Org.
Lett. 2014, 16, 3600–3603. (i) Li, Y.-L.; Li, J.; Yu, S.-N.; Wang,
J.-B.; Yu, Y.-M.; Deng, J. Tetrahedron 2015, 71, 8271–8277. (j)
Li, P.; Weng, Y.; Xu, X.; Cui, X. J. Org. Chem. 2016, 81,
Acknowledgments
This research work was supported in part by grants from
Chulabhorn Research Institute (CRI), Chulabhorn Graduate
Institute (CGI), Mahidol University, the Center of Excellence on
Environmental Health and Toxicology, Science & Technology
Postgraduate Education and Research Development Office
(PERDO), Ministry of Education. We would also like to
gratefully acknowledge the assistance in this work by Mr.
Auttaphon Chachavalvuttikul (2016 undergraduate summer
intern from Chiang-Mai University, Chiang-Mai, Thailand) and
Mr. Itthinan Duangngam (2017 undergraduate summer intern
from Chulalongkorn University, Bangkok, Thailand).
−4001.
3994
6. For preparation of compound 1a, and other compounds, as well as
their characterization data, please see supporting information.
7. (a) Müller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675–703. (b)
Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem. Int. Ed.
2004, 43, 3368–3398. (c) Chianese, A. R.; Lee, S. J.; Gagné, M.
R. Angew. Chem. Int. Ed. 2007, 46, 4042–4059.
8. For some recent examples, please see: (a) Fürstner, A.; Hannen, P.
Chem. Eur. J. 2006, 12, 3006–3019. (b) Lu, L.; Liu, X.-Y.; Shu,
X.-Z.; Yang, K.; Ji, K.-G.; Liang, Y.-M. J. Org. Chem. 2009, 74,
474–477. (c) McAdam, C. A.; McLaughlin, M. G.; Johnston, A. J.
S.; Chen, J.; Walter, M. W.; Cook, M. J. Org. Biomol. Chem.
2013, 11, 4488–4502. (d) Kwon, Y.; Kim, I.; Kim, S. Org. Lett.
2014, 16, 4936−4939.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at
9. The generation of HCl and the HCl-induced proto-deplatination of
reactions involving organoplatinum species within a catalytic
cycle have been studied and proposed previously, please see: (a)
Kong, W.; Cui, J.; Yu, Y.; Chen, G.; Fu, C.; Ma, S. Org. Lett.
2009, 11, 1213–1216. (b) Bender, C. F.; Brown, T. J.;
Widenhoefer, R. A. Organometallics 2016, 35, 113−125.
References and note
1. (a) The Chemistry of Heterocyclic Compounds; Taylor, E. C.,
Saxton, J. E., Eds.; Wiley-Interscience: New York, 1983; Vol. 25.
(b) Sundberg, R. J. In Indoles; Academic Press: New York, 1996.
(c) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761–793.
(d) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin.
Chem. Biol. 2010, 14, 347–361. (e) Kaushik, N. K.; Kaushik, N.;
Attri, P.; Kumar, N.; Kim, C. H.; Verma, A. K.; Choi, E. H.
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Tetrahedron
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PtCl4-Catalyzed cyclization of N-acetyl-2-
alkynylanilines: a mild and efficient synthesis of
N-acetyl-2-substituted indoles
Nattawadee Chaisan, Wilailak Kaewsri, Charnsak Thongsornkleeb, Jumreang Tummatorn, Somsak Ruchirawat
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PtCl4-Catalyzed cyclization of N-acetyl-
2-alkynylanilines: a mild and efficient
synthesis of N-acetyl-2-substituted
indoles
Nattawadee Chaisan,a Wilailak Kaewsri,a Charnsak
Thongsornkleeb,a,b,* Jumreang Tummatorn,a,c and
Somsak Ruchirawata,c
a
Program on Chemical Biology, Chulabhorn Graduate Institute, Center of
Excellence on Environmental Health and Toxicology (EHT), Ministry of
Education, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand.
b
Laboratory of Organic Synthesis, Chulabhorn Research Institute, 54
Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand.
c Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54
Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand.
Highlights
•
PtCl4 is an efficient catalyst for
intramolecular cyclization of 2-
alkynylanilines.
•
•
•
•
A variety of 2-substituted indoles are
synthesized in moderate to excellent yields.
The procedures can be easily applied to a
wide scope of easily prepared substrates.
Only 1-2 mol% loading of PtCl4 is required
for efficient and effective conversions.
The current protocol is applicable to gram-
scale preparation of indole derivatives.