Platinum-catalyzed selective N-allylation of 2,3-disubstituted indoles with allylic acetates in water

Article abstract of DOI:10.1039/c8nj05051a

Due to their biological activity, indoles and substituted indoles have attracted considerable attention from both synthetic and medicinal scientists. Much effort has been directed toward the development of methods for the functionalization of the indole nucleus. The protocol uses a catalytic amount of catalyzed platinum as a promoting agent, producing N-allylated indoles in considerable yields. Moreover, water, with its large heat capacity, is one of the most abundant molecules on earth. The use of water as a solvent may bring about many environmental benefits. Herein, we have demonstrated that the platinum-catalyzed selective N-allylation of 2,3-disubstituted indoles proceeds in water. This method provides a simple, convenient, and efficient way to afford a high yield of N-allylated indoles.

Full text of DOI:10.1039/c8nj05051a

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
NJC
View Article Online
View Journal | View Issue
PAPER
Platinum-catalyzed selective N-allylation of
2,3-disubstituted indoles with allylic acetates
in water†
Cite this: New J. Chem., 2019,
43, 58
ab
b
Bai-Jing Peng,
Wen-Ting Hsueh,a Ferenc Fulop
¨ ¨
and Shyh-Chyun Yang*acd
Due to their biological activity, indoles and substituted indoles have attracted considerable attention
from both synthetic and medicinal scientists. Much effort has been directed toward the development
of methods for the functionalization of the indole nucleus. The protocol uses a catalytic amount of
catalyzed platinum as a promoting agent, producing N-allylated indoles in considerable yields. Moreover,
water, with its large heat capacity, is one of the most abundant molecules on earth. The use of water as a
solvent may bring about many environmental benefits. Herein, we have demonstrated that the platinum-
catalyzed selective N-allylation of 2,3-disubstituted indoles proceeds in water. This method provides a
simple, convenient, and efficient way to afford a high yield of N-allylated indoles.
Received 5th October 2018,
Accepted 5th November 2018
DOI: 10.1039/c8nj05051a
rsc.li/njc
Heck, and Negishi couplings are essential, as recorded by the
2010 Nobel Prize.6 The palladium-catalyzed allylation of nucleo-
Introduction
The asymmetric structure synthesis of N-allylic indoles is philes has been proven to be an efficient, established, and highly
crucial for natural alkaloid synthesis and organic materials chemo- and stereo-selective method.7 The catalytic cycles have
research.1 Particularly, indoles and indole-derived heterocycles been shown to proceed via the attack of nucleophiles on cationic
consist of a 2,3-disubstituted construction in medicinal drugs.2 Z3-allylpalladium(II) complexes, an intermediate generated by the
As a result, extensive functionalization efforts have been under- oxidative addition of allylic compounds, including carbamates,
taken to develop catalytic asymmetric allylation of indole nuclei carbonates, esters, halides, phosphates, and related derivatives,
at the N1 or C3 sites.3 Nevertheless, the allylation attack at the to a Pd(0) complex.7c,8 Ruthenium, as well as palladium, have
N1 site on 2,3-disubstituted indoles to produce N-allylated been used in the allylation reaction of 2,3-disubstituted indoles,
indoles containing a new carbon–nitrogen bond is a difficult but according to our knowledge, the use of platinum is rare.9
transformation because of the high nucleophilicity of the C3 Platinum is a good transition metal, which is not often
site of the indole nucleus and the weak acidity of the N–H discussed.10 During our previous research on allylation with
bond.4 For these reasons, efficient strategies for the synthesis platinum as a catalyst agent, we established the application of
of N-allylic 2,3-disubstituted indoles are still rare.4a Given the processed platinum catalysis with desirable data.11
importance of N-allylation of 2,3-disubstituted indoles, we have
been attracted toward this aspect of research.
In recent years, our team has reported the Pt(II)-catalyzed
allylation of 2,3-disubstituted indoles in benzene.12 However,
Transition metal catalysis has been and continues to be a benzene is a highly flammable and toxic liquid with a sweet
predominant tool to form carbon–carbon, carbon–nitrogen, smell, and increases the risk of cancer and other illnesses.13 In
carbon–oxygen, and carbon–heteroatom bonds in organic syn- this scenario, considering both green chemistry and safety, it is
thesis.5 In particular, palladium-catalyzed Suzuki–Miyaura, crucial to find an alternative, environmentally-friendly solvent.14
Organic reactions in water have attracted much attention,
because water is inexpensive, nonflammable, nontoxic, and
a School of Pharmacy, College of Pharmacy, Kaohsiung Medical University,
has a large heat capacity.15 Water in its pure form is completely
Kaohsiung 807, Taiwan
benign, so it would appear to be an attractive solvent.16 Therefore,
b
¨
¨
Institute of Pharmaceutical Chemistry, University of Szeged, Eotvos u. 6,
H-6720 Szeged, Hungary
the development of atom-economic reactions in water is one of
the most important objectives of synthetic chemistry.11a,17 In
this paper, we intend to disclose our study of the N-allylation of
indoles with allylic acetates in the presence of a catalytic amount
of platinum/phosphine complexes. The protocol allowed the
N-selectivity of the reaction in water to be effectively controlled.
c Department of Fragrance and Cosmetic Science, College of Pharmacy,
Kaohsiung Medical University, Kaohsiung 807, Taiwan
d Department of Medical Research, Kaohsiung Medical University Hospital,
Kaohsiung 807, Taiwan. E-mail: scyang@kmu.edu.tw; Tel: +886-918-665-770
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8nj05051a
58 | New J. Chem., 2019, 43, 58--62
This journal is ©The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
View Article Online
Paper
NJC
This reaction system created a simple, convenient, and efficient acetate (2a, 2 mmol) was refluxed in the presence of catalytic
way to afford a high yield of N-allylated indoles in water.
amounts of Pt(acac)2 (2.5 mmol%) and PPh3 (10 mmol%) in
water for 2 h, N-allyl-1,2,3,4-tetrahydrocarbazole (3a) was formed
in only 28% yield (entry 1 in Table 1). In initial studies, we
examined the effectiveness of commercial sources for the ligands.
Among the monodentate ligands inclusive of PPh3 (entry 1),
Results and discussion
The platinum-catalyzed allylation of 2,3-disubstituted indoles, (2-furyl)3P (entry 2), (2-CH3C6H4)3P (entry 3), (3-CH3C6H4)3P
such as 1,2,3,4-tetrahydrocarbazole, with allyl acetate was (entry 4), (4-CH3C6H4)3P (entry 5), (4-FC6H4)3P (entry 6),
investigated under different scenarios (Scheme 1). When a (4-ClC6H4)3P (entry 7), (4-CH3OC6H4)3P (entry 8), (n-butyl)3P
mixture of 1,2,3,4-tetrahydrocarbazole (1a, 1 mmol) and allyl (entry 9), [2,4,6-(CH3O)3C6H2]3P (entry 10), (2-pyridyl)Ph2P (entry 11),
Scheme 1 Allylation of 1,2,3,4-tetrahydrocarbazole (1a) with allyl acetate (2a).
Table 1 Reaction of 1,2,3,4-tetrahydrocarbazole (1a) with allyl acetate (2a)a
Entry
Ligand
Platinum catalyst
Solvent
Yield (%) (3a + 4a)
Yieldb (%) of 3a
Yieldb (%) of 4a
1
2
3
4
5
6
7
8
PPh3
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
28
2
3
17
9
18
95
8
12
8
4
5
19
7
28
2
3
17
0
14
95
0
12
0
4
5
19
7
5
6
29
0
67
70
0
86
72
12
68
13
9
0
0
0
0
9
4
0
8
0
8
0
0
0
0
0
7
0
0
0
0
0
7
10
0
21
0
3
9
3
11
0
0
0
0
24
19
31
0
(2-Furyl)3P
(2-CH3C6H4)3P
(3-CH3C6H4)3P
(4-CH3C6H4)3P
(4-FC6H4)3P
(4-ClC6H4)3P
(4-CH3OC6H4)3P
(n-Butyl)3P
[2,4,6-(CH3O)3C6H2]3P
(2-Pyridyl)Ph2P
[2,6-(CH3O)2C6H3]3P
BINAP
9
10
11
12
13c
14d
15e
16 f
17g
18
19h
20i
21
22
23
24
25
26
27
28
29
30
31
32
33 j
34k
35
36
37
38
39
dppf
dppb
dppm
dppe
5
12
29
0
67
70
0
93
82
12
89
13
12
9
11
34
3
11
50
60
34
28
34
17
26
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
—
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
—
—
cis-PtCl2(PhCN)2
cis-PtCl2(PPh3)2
Pt(COD)Cl2
O[Si(CH3)2CQCH2]2Pt
PtCl2
PtI2
Pt(CN)2
Pt(CH2QCH2)(PPh3)2
Pt(CH2QCH2)(PPh3)2
Pt(PPh3)4
Pt(PPh3)4
Pt(acac)2
Pt(acac)2
Pt(acac)2
0
8
(4-ClC6H4)3P
—
23
3
11
50
60
10
9
2
17
26
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
(4-ClC6H4)3P
H2O
H2O
Benzene
Toluene
CH2Cl2
CH3OH
C2H5OH
Pt(acac)2
Pt(acac)2
Pt(acac)2
Pt(acac)2
0
a
b
Reaction conditions: 1a (1 mmol), 2a (2 mmol), Pt catalyst (0.025 mmol), and ligand (0.1 mmol) in solvent (5 mL) were refluxed for 2 h. Isolated yield.
c
d
e
f
(ꢀ)-2,20-Bis(diphenylphosphino)-1,10-binaphthalene. 1,1-Bis(diphenylphosphino)ferrocene. 1,4-Bis(diphenylphosphino)butane. 1,1-Bis(diphenyl-
phosphino)methane. 1,2-Bis(diphenylphosphino)ethane. Stirred at 80 1C. Refluxed for 1 h. j (4-ClC6H4)3P (0.05 mmol). k 2a (1.2 mmol).
g
h
i
This journal is ©The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019
New J. Chem., 2019, 43, 58--62 | 59

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
View Article Online
NJC
Paper
Table 2 Reaction of 1,2,3,4-tetrahydrocarbazole (1a) with allylic com-
pounds (2b–f)a
and [2,6-(CH3O)2C6H3]3P (entry 12) were used. In addition,
bidentate ligands including BINAP (entry 13), dppf (entry 14),
dppb (entry 15), dppm (entry 16), and dppe (entry 17) were
evaluated in the reaction. The catalytic reactivity of the ligand
(4-ClC6H4)3P was likely due to improved catalyst stability and
produced N-allylation product 3a in a 95% yield (entry 7). It was
obvious that the predominant product was N-allylated 1,2,3,4-
tetrahydrocarbazole. In the absence of a ligand, the reaction did
not occur (entry 18). The surrounding reaction conditions were
also investigated. It was confirmed that when the temperature of
the reaction was decreased, the yield also decreased (entry 19).
Not only the temperature, but also reaction time affected the
yield. As expected, as the reaction time became shorter, the
yield of the predominate N-allylation derivative decreased too
(entry 20). In the presence of various platinum catalysts, including
Pt(acac)2 (entry 7), cis-PtCl2(PhCN)2 (entry 22), cis-PtCl2(PPh3)2
(entry 23), Pt(COD)Cl2 (entry 24), O[Si(CH3)2CQCH2]2Pt (entry 25),
PtCl2 (entry 26), PtI2 (entry 27), Pt(CN)2 (entry 28), Pt(CH2QCH2)-
(PPh3)2 (entries 29 and 30), and Pt(PPh3)4 (entries 31 and 32),
it was shown that the most effective platinum catalyst and
the most regioselective for N-allylation is Pt(acac)2 (entry 7).
However, using Pt(CH2QCH2)(PPh3)2 or Pt(PPh3)4 with extra
(4-ClC6H4)3P as a catalyst increased the yields of the products
(entries 30 and 32). The reaction would not occur without any
platinum species as a catalyst (entry 21). During the reaction,
adding phosphine ligands could increase the activity of the
platinum catalyst. A reduction in the ratio of Pt(acac)2 to
(4-ClC6H4)3P, to a ratio of 1 : 2 (entry 33), decreased the yield
of the reaction. Decreasing the relative amounts of allyl acetate
disfavored the formation of product 3a (entry 34). It was known
Entry
2
Yieldb (%)
1
2
3b 71 (E/Z = 89/11)d
4b 2
3
4
3c 81 (E/Z = 85/15)d
4c 0
5
6c
3a 12
3a 57
4a 0
4a 0
2f
7
3a 92
4a 5
a
Reaction conditions: 1a (1 mmol), 2a (2 mmol), Pt(acac)2 (0.025 mmol),
and (4-ClC6H4)3P (0.1 mmol) in solvent (5 mL) were refluxed for 2 h.
b
d
c
Isolated yield. Pt(acac)2 (0.05 mmol) and (4-ClC6H4)3P (0.2 mmol).
Determined by GC.
that several factors, such as the solvent and the nature of the that the C-3 position products, which were involved in the
nucleophile, could alter the product pattern in metal-catalyzed internal N-allylation, were not generated in this scenario. More-
allylation. Six solvents were investigated (entries 7 and 35–39). over, the reaction was considered to proceed via p-allylplatinum
To our surprise, when the reaction used an organic solvent like intermediates. The loss of stereochemistry in the starting acetate
benzene, toluene, or dichloromethane, the C-allylation product 2b was due to the more rapid s 2 Z3 2 s interconversion of
yield was more superior to that of the N-allylation products the intermediates compared to the rate of allylation. trans-2-
(entries 35–37). In particular, the C-allylation product was the Hexen-1-yl acetate (2d), which reacted with 1a, gave 3c and 4c in
prominent product for reactions with dichloromethane as the 69% and 3% yields, respectively (entry 3). In the reaction of
solvent. Apart from this, the appropriate solvent for the reaction hex-1-en-3-yl acetate (2e), the corresponding N-allylated products
is water. Remarkably, no C-allylation products were detected were formed in 81% overall yields (entry 4). Unfortunately, the
in water.
reaction of allyl chloride (2e), which is not an appropriate reagent
The outcomes of the reaction conditions examined above for allylation, only produced 3a in a yield of 12% (entry 5).
were found to be applicable to a wide variety of allylic com- Increasing the amount of the reagents Pt(acac)2 and (4-ClC6H4)3P to
pounds. The results for the allylation of a number of allylic twice the original dose could improve yields of 3a up to 57%
compounds (2b–g) with 1,2,3,4-tetrahydrocarbazole (1a) using (entry 6). The catalyst could not affect the yield, but this concept
Pt(acac)2 and (4-ClC6H4)3P are compiled in Table 2. The allylation was built on the use of a sufficient amount of catalyst. In our
of 3-buten-2-yl acetate (2b) gave N-allylated tetrahydrocarbazole catalyst system, we established N-allylation with trace amounts
3b in a yield of 86% (entry 1). The N-allylated tetrahydrocarbazole of platinum. Last but not least, with allyl carbonate (2g), the
E/Z ratio of 3b was determined by GC. Obviously, the E alkene reaction afforded 3a and 4a in a 97% overall yield (entry 7). 3a
product was generated from the more thermodynamically- was still the dominant product and was obtained in a yield of
stable syn complex. It was in a 73% overall yield that the corre- 92% in the allylation of 2g.
sponding reaction with crotyl acetate (2c) afforded N-allylated
The good efficiency of the allylation reactions described
and C-allylated tetrahydrocarbazole (entry 2). These N-allylated above prompted us to extend the reaction to corresponding
products might all originate from the same p-allylic intermediate, indole derivatives (Table 3). The results summarized in Table 3
which could be attacked at the C-1 position. The formation of showed that the allylation of allyl acetaete (2a) with indoles,
the regioisomeric product was not observed. It is probable using Pt(acac)2 and (4-ClC6H4)3P, gave generally good yields of a
60 | New J. Chem., 2019, 43, 58--62
This journal is ©The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
View Article Online
Paper
NJC
Table 3 Allylation of indoles (1) with allyl acetate (2a)a
Entry
1
Yieldb (%)
1
2
3
4
Scheme 2 Proposed mechanism.
with indole 6. Then, the whole system gives N-allyl-2,3-disubstituted
indole 3.
Conclusions
In conclusion, we have shown that the platinum(0)-catalyzed
allylation of allylic acetates using heterocycle fused indoles is
a simple, convenient, and efficient way to achieve C–N bond
formation. The reaction did not occur in the absence of a platinum
catalyst and phosphine ligands. It is obvious that the best solvent
is water in the reaction. The allylation of allylic acetates worked
well with carbazoles, giving generally good yields of the corres-
ponding allylic carbazoles.
5
a
Reaction conditions: 1a (1 mmol), 2a (2 mmol), Pt(acac)2 (0.025 mmol),
and (4-ClC6H4)3P (0.1 mmol) in solvent (5 mL) were refluxed for 2 h.
b
Isolated yield.
variety of allylic indoles (entries 1–5). First, the allylation of the
simpler 3-methylindole 1b was investigated. The overall yield
was 73% (entry 1). 2,3-Dimethyl indole (1c) was a desirable
substrate and generated N-allylated tetrahydrocarbazole in a
92% yield (entry 2). 1,2-Dimethyl-3H-benzoindole (1d), which
consisted of the substituted benzene ring of tetrahydrocarb-
azole, was well tolerated and gave 96% yields of the corres-
ponding N-allylated products (entry 3). The cyclopentane- and
cycloheptane-fused indoles 1e and 1f participated in the reac-
tion and gave high yields of the corresponding N-allylated com-
pounds (entries 4 and 5).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by a grant from the National Science
Council of the Republic of China (NSC101-2113-M-037-008-MY3).
A possible mechanism for the formation of N-allyl-2,3-
disubstituted indoles from 1 and 2 is illustrated in Scheme 2,
in which the substituent on allylic acetate is omitted. The circu-
lation indicates that a Pt(II)-assisted mechanism is the feasible
mechanism for C–N formation and activation. The entire path-
way consists of three steps: allyl acetate 2 with Pt(0)Ln, allyl-
ation of the 2,3-disubstituted indole, and elimination from the
p-allylplatinum intermediate. As detailed, 2 reacts with Pt(0)
and the phosphine ligand species, which generate in situ, to
produce p-allylplatinum intermediate 5. Subsequently, the reac-
tion of 5 with 2,3-disubstituted indole 1 gives the p-allylplatinum
intermediate with indole 6. Finally, the C–N bond formation is
followed by the elimination of the p-allylplatinum intermediate
Notes and references
1 (a) H. Yan, H. Wang, X. Li, X. Xin, C. Wang and B. Wan, Angew.
Chem., Int. Ed., 2015, 54, 10613–10617; (b) M. C. Tong,
X. Chen, J. Li, R. Huang, H. Tao and C. J. Wang, Angew.
Chem., Int. Ed., 2014, 53, 4680–4684; (c) W. Gul and M. T.
Hamann, Life Sci., 2005, 78, 442–453.
2 (a) N. Chadha and O. Silakari, Eur. J. Med. Chem., 2017, 134,
159–184; (b) E. V. Villemson, E. M. Budynina, O. A. Ivanova,
D. A. Skvortsov, I. V. Trushkov and M. Y. Melnikov, RSC Adv.,
2016, 6, 62014–62018; (c) G. W. Gribble, Indole ring synthesis:
From natural products to drug discovery, John Wiley & Sons,
2016.
This journal is ©The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019
New J. Chem., 2019, 43, 58--62 | 61