Palladium-catalyzed selective N -allylation of indoles assisted by PEG-water system

Article abstract of DOI:10.1039/c9nj02335f

The synthesis of N-allylic indoles is of great interest because of their potential biological properties. It is a true challenge to develop new methods for the N-allylation of indoles due to the favorable C3-allylation. We uncovered a new strategy to synthesize N-allylic indoles via a palladium catalyst as a promoting agent, providing the N-allylated indoles in high yields. In addition, the organic reaction with polyethylene glycol (PEG) in water is one of the key emerging strategies that is currently attracting tremendous attention, which is intended to provide alternative eco-friendly and efficient ways for the construction of covalent bonds. In this study, the palladium-catalyzed indoles with allylic acetates in a PEG-water system were investigated under various conditions. This system provides a simple, convenient, and efficient way to afford a high yield of N-allylated indoles.

Full text of DOI:10.1039/c9nj02335f

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DOI: 10.1039/C9NJ02335F
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Palladium-Catalyzed Selective N-Allylation of Indoles Assisted by
PEG-Water System
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Bai-Jing Peng , Yi-Ting Huang , Ferenc Fülöp , I-Ling Lin and Shyh-Chyun Yang *
Received 00th January 20xx,
Accepted 00th January 20xx
The synthesis of N-allylic indoles is privileged structures because of their potential biological properties. It is a true challenge
to develop new methods for N-allylation of indoles due to the favorable C3-allylation. We uncover a new strategy to
synthesize N-allylic indoles via palladium-catalyzed transition metal as a promoting agent, providing N-allylated indoles in
wonderful yields. In addition, organic reaction with polyethylene glycol (PEG) in water is one of the key emerging strategies
that is currently attracting tremendous attention intending to provide alternative eco-friendly and efficient ways for the
construction of covalent bonds. In this study, the palladium-catalyzed indoles with allylic acetates in PEG-water system were
investigated under various conditions. This system provides a simple, convenient, and efficient way which afforded a high
yield of N-allylated indoles.
DOI: 10.1039/x0xx00000x
because it is non-toxic, naturally biodegradable, and potentially
8
reusable. PEG also plays an essentially important role in
Introduction
9
coordinating with many metal centers to form stable complexes.
In the previous work, our teams have published the topic with
The synthesis of indole derivatives has attracted much scientists’
desirable data: the use of platinum as a transition metal catalyzing
1
attention in fields of both chemistry and pharmacy. Not only do
10
the allylation of 2,3-disubstituted indoles. However, compared to
indoles bear important structure motifs at the N position, but also
palladium, platinum is more expensive as a catalytic reagent and less
contain a variety of bioactivities in comprehensive pharmaceutical
11
abundant on earth. In light of this scenario and the consideration
2
medicines and natural products (Figure 1). Therefore, given the
of green chemistry, it is better to choose palladium as the transition
importance of indole nucleus in activity, it is crucial to explore an
12
metal catalyst instead of platinum. Also, admittedly, the organic
3
appropriate catalytic system in allylation of indoles. It is a vital
reaction in an eco-friendly solvent, especially water, has attracted
much attention due to its inexpensive, nontoxic, and nonflammable
challenge to generate N-allylated indoles including a carbon-nitrogen
bond by allylation attacking at the N1 site on indole heterocycles due
to the N-H bond with weak acidity and the C3 site with high
13
traits. Water in its pure form is completely benign with large heat
14
capacity, hence it would appear to be an attractive solvent.
4
nucleophilicity in the indole nucleus (Scheme 1). As a result, direct
Accordingly, the development of atom-economic allylation reactions
in water is one of the most important objectives of synthetic
allylation of 2,3-disubstituted indoles to produce N-allylic 2,3-
2a
disubstituted indoles are still rare.
15
chemistry.
In organic allylation synthesis, it has been provided a useful
methodology and a predominant tool that palladium as transition-
metal-catalyzed system forms carbon–carbon, carbon–nitrogen,
Herein, we disclose our findings that readily available
palladium/phosphine complexes in combination with PEG are an
extremely effective catalyst for the N-allylation of indoles with allylic
acetates. The protocol provides a simple, convenient, and efficient
way to afford a high yield of selective N-allylated indoles in water.
5
carbon–oxygen, and carbon–heteroatom bonds. The concept of
palladium as a catalyst has been established, when Heck et al. have
disclosed their prominent work on this subject since 1974. Nowadays,
a vast number of allylation protocols with palladium-catalyzed
6
OH
O
reagent is available for C-N bond formation. Moreover, when using
transition metal as a catalyst considering green chemistry, it is
certain to avoid hazardous reagent and to react in the H3CO
environmentally-friendly additive such as polyethylene glycol (PEG).
PEG, in contrast to common media, has gained much attraction
H
7
CH3
N
N
HO
O
N
N
O
O
N
a. School of Pharmacy, College of Pharmacy, Kaohsiung Medical University,
Kaohsiung 807, Taiwan
Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, H-6720
Cl
b.
c.
d.
e.
Indomethacin
Anti-inflammatory
Binedaline
Antidepressdant
Vincamine
Vasodilator
Szeged, Hungary
Department of Medical Laboratory Science and Biotechnology, College of Health
Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung
Medical University, Kaohsiung 807, Taiwan
Figure 1. Biologically active N-substituted indoles
Department of Medical Research, Kaohsiung Medical University Hospital,
Kaohsiung 807, Taiwan. Email: scyang@kmu.edu.tw; Tel:+886-918-665-770
Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
†
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PEG-600
PEG-800
71
74
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View Article Online
57 DOI: 10.103197/C9NJ02335F
C-allylation
favored
PEG-2000 66
PEG-4000 78
PEG-6000 87
PEG-6000 84
PEG-6000 70
PEG-6000 25
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H
c
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e
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a
N
Reaction conditions: 1a (1 mmol), 2a (2 mmol), Pd(OAc)
(0.025
2
H
mmol), (2-furyl) P (0.05 mmol), and PEG (1 g) in water (5 mL)
3
b c d
were refluxed for 2 h. Without PEG PEG-6000 (2 g). PEG-
e
6
000 (0.5 g). Benzene as the solvent.
N-allylation
unfavored
N
With the optimized PEG conditions in hand, we then examined
the scope of the addition of different ligands featuring either an
electron-releasing or an electron-withdrawing group in Table 2. The
phosphine ligand played an important role in the allylation, which
stabilized Pd(0) and let the reaction occur fluently. It was confirmed
that the allylation couldn’t process without any ligand (entry 1). The
PPh3 only gave a 3% yield (entry 2). The electron-rich methyl
substrates like (4-CH C H ) P and (2-CH C H ) P afford higher C-
3 6 4 3 3 6 4 3
allylation derivative yields than N-allylation (entries 3 and 4). On the
other hand, there were low yields in the allylation with either (4-
Scheme 1. Known struggle
Results and Discussion
To evaluate our assumption, our studies began with the allylation
of 1,2,3,4-tetrahydrocarbazole and allyl acetate in the presence of
Pd(OAc) (2.5 mmol%), (2-furyl) P (5.0 mmol%), and PEG-400 (1 g) in
2 3
water (5 mL) (Scheme 2). Among the polyethylene glycol inclusive of
PEG-400 (entry 1), PEG-600 (entry 3), PEG-800 (entry 4), PEG-2000
CH
and 6). As for the electron-withdrawing groups such as (4-FC
and (4-ClC
electron-rich substrates (entries 7 and 8). Obviously, the (2-furyl)
3 6 4 3 3 6 3 3
OC H ) P or (2,6-diCH OC H ) P as methoxyl groups (entries 5
6
H
4
)
3
P
6 4
H )
3
P, both of them were found to be more effective than
3
P
(
entry 5), PEG-4000 (entry 6), and PEG-6000 (entry 7) were evaluated
in Table 1. Surprisingly, the undesired N1-selective product, N-allyl-
,2,3,4-tetrahydrocarbazole (3a) was isolated with a low 2% yield.
still gave the highest yields among all ligands (entry 9). Reducing the
dosage of the (2-furyl) P caused a drop in both N-allylated and C-
1
3
allylated yields (entry 10).
The isomer of 3a is 4a-allyl-2,3,4,4a-tetrahydro-1H-carbazole (4a) in
the yield of 8% (entry 1). However, the total yields were 24% more
than entry 1 with PEG-400 in the absence of polyethylene glycol
(entry 2). We predicted that the PEG-400 was not suitable in the
allylation of indoles. The PEG-600 with the same liquid phase of PEG-
1
R = H
R1
O
P
1
R = 4-CH3
1
R = 2-CH3
4
00 afforded the total yields 71% (entry 3). There was a 74% yield in
P
R1
1
R = 4-CH3O
O
O
the reaction of PEG-800 (entry 4). Compared to the solid phase, we
were pleased to observe that PEG-6000 had the best production in
the total 87% yields among all of the PEGs. It was obvious that the
predominant product was N-allylated 1,2,3,4-tetrahydrocarbazole.
To improve N-allylation derivative, the dose of PEG-6000 was under
examination (entry 8 and entry 9). When using PEG-6000 with 2
grams, the total yields decreased down, but C-allyated production
increased (entry 8). Reducing the dose of PEG-6000 down to 0.5
grams got the low yields (entry 9). The amount of PEG-6000 could
R1
1
R = 2,6-diCH3O
1
R = 4-F
1
R = 4-Cl
(2-Furyl)3P
Table 2. Optimization of ligand.a
Yield (%) of Yield (%)
Yield (%)
of 4a
0
0
16
16
0
Entry Ligand
(
3a + 4a)
0
3
20
18
2
of 3a
1b
2
3
4
5
0
3
4
2
2
-
PPh
3
(
4-CH
3
C
C
6
H
H
4
)
)
3
P
P
not affect the N-allylated yields. Besides, replacing H
the total allylation yields were low (entry 10).
2
O with benzene,
(2-CH
3
6
4
3
(4- CH
2,6-
diCH OC H ) P
3 6 4 3
OC H ) P
(
6
1
1
0
OAc
3
6 3 3
2
a
7
8
9
1
a
6 4
(4-FC H )
3
P
54
51
87
54
34
34
68
34
20
17
19
20
N
N
N
H
Pd(OAc)2, (2-furyl)3P
(4-ClC H ) P
6
4 3
PEG-400, H2O
o
(2-Furyl)
(2-Furyl)
3
P
P
1a
3a
4a
1
00 C, 2 h
0c
3
Reaction conditions: 1a (1 mmol), 2a (2 mmol), Pd(OAc)
2
(0.025
Scheme 2. Allylation of 1,2,3,4-tetrahydrocarbazole (1a) with allyl
acetate (2a)
mmol), ligand (0.05 mmol), and PEG-6000 (1 g) in water (5 mL)
b
c
were refluxed for 2 h. Without ligand. (2-Furyl)
3
P (0.025
mmol).
Table 1. Optimization of polyethylene glycol.a
Yield (%) of
(3a + 4a)
10
24
Yield (%)
of 3a
Yield (%)
of 4a
8
0
In order to raise the production of N-selectivity on indoles, the
scope of palladium catalyst effect was evaluated in Table 3. In the
presence of various palladium catalysts, including Pd(OAc) (entry 1),
2
Entry PEG
1
2
PEG-400
2
b
-
24
2
| J. Name., 2012, 00, 1-3
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Pd(acac)
Pd(OCOCF
), PdCl (1,10-phen)
entry 11), Pd(PPh
shown that Pd(OCOCF
could afford the total N-allylation and C-allylation production higher 8).
than 90% yields. The Pd(PPh included PPh originally. However,
reacted with Pd(PPh alone without extra ligand (2-furyl) P, the
total yields only gave 12%. During the reaction, adding (2-furyl)
would enhance the activity of Pd(PPh . Apart from this, the most
2
(entry 3), Pd(propionate)
(entry 6), PdCl (MeCN)
(entry 9), Pd(hfacac)
, (entry 12), and [Pd(allyl)Cl]
, Pd(hfacac) , Pd(PPh
2
(entry 4), PdCl
(entry 7), PdCl (PhCN)
(entry 10), Pd
(entry 13), it was of the reagents Pd(OCOCF
2
(entry 5),
2
methylbut-2-en-1-yl acetate (2g) which only generatVeiedw3Areticilne O4n7lin%e
(entry yield (entry 6). The allyl chloride (2h), which DwOaIs: 1n0o.1t0a39g/oCo9dNrJe0a2g3e35nFt
3
)
2
2
2
2
8
(
2
2
2
2
(dba)
3
for allylation produced 3a (up to 72%) under increasing the amount
and (2-furyl) P to twice dose (entry 7).
With allyl carbonate (2i), the reaction afforded 3a in 97% yield (entry
3
)
4
2
3
)
2
3
3
)
2
2
3
)
4
, and [Pd(allyl)Cl]
2
3
)
4
3
3
)
4
3
0
1
2
3
4
5
6
7
8
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0
1
2
3
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7
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0
1
2
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
P
Table 4. Scope of the N1-selective allylation of 1,2,3,4-
a
3
)
4
tetrahydrocarbazole (1a) with allylic compounds (2b-i).
effective palladium catalyst for N-allylation was Pd(OCOCF
gave the N-allylated production up to 96% yield (entry 6).
3
)
2
which
b
Entry
2
Yield (%)
N
Table 3. Optimization of palladium.a
AcO
1
Yield (%) of
3a + 4a)
Yield (%)
of 3a
68
Yield (%)
2b
Entry Pd catalyst
(
87
0
71
78
88
98
76
89
of 4a
19
0
N
3b 84
4
b 0
1
2
3
4
5
6
7
8
Pd(OAc)
-
2
d
d
b
(E/Z=88/12)
0
Pd(acac)
Pd(propionate)
PdCl
Pd(OCOCF
2
38
59
50
96
62
58
33
19
38
2
14
31
3b 85
2
3
AcO
4b 2
(E/Z=90/10)
2
2
c
2
3
)
2
PdCl
PdCl
PdCl
2
2
2
(MeCN)
(PhCN)
(1,10-
2
N
2
OAc
9
57
24
33
2d
phen)
Pd(hfacac)
Pd (dba)
Pd(PPh
[Pd(allyl)Cl]
Pd(PPh
2
1
1
1
1
1
0
1
2
3
4
2
96
70
91
94
12
80
57
79
64
12
16
13
12
30
0
N
3
c 77
2
3
4c 3
d
d
(
E/Z=89/11)
3 4
)
OAc
2
3c 81
4
5
4c 0
c
3
)
4
(E/Z=88/12)
2
e
a
Reaction conditions: 1a (1 mmol), 2a (2 mmol), Pd catalyst (0.025
mmol), (2-furyl) P (0.05 mmol), and PEG-6000 (1 g) in water (5 mL)
were refluxed for 2 h. Without Palladium catalyst. Without (2-
furyl) P.
3
b
c
N
AcO
3
2
f
N
4
d 0
To further showcase the versatility of our method, we sought to
tackle the allylation of 1,2,3,4-tetrahydrocarbazole as 2,3-
disubstituted with a wide variety of allylic compounds in Table 4. In
the case of crotyl acetate (2b) (entry 1), an exclusive N-allylated
tertahydrocarbazole was formed into the desired amount in 84%
yield. The N-allylated tetrahydrocarbazole E/Z ratio of 3b was
analyzed by GC. While the branched profile of 3-buten-2-yl acetate
3d 74
N
6
OAc
2g
N
5e 0
3
e 46
(
2c) was yet to be explored, the superior product of straight chain
Cl
7c
8
3a 72
4a 0
was N1-selective indoles in the yield of 85% (entry 2). The E alkene
product was generated from the more thermodynamically-stable syn
complex. These N1-selective products would all be originated from
the same intermediate, π-allylic compound which could be attacked
at the C-1 position. The formation of the regioisomeric product was
not detected. It was probable that the C-3 position products, which
involved in the internal N-allylation, were not generated in this
system. Moreover, the reaction was considered to proceed via π-
allylpalladium intermediates. The loss of stereochemistry of starting
2
h
O
O
O
3a 97
4a 0
2
i
a
Reaction conditions: 1a (1 mmol), 2 (2 mmol), Pd(OCOCF
(0.025 mmol), (2-furyl)
water (5 mL) were refluxed for 2 h Isolated yield. Pd(OCOCF
3
)
2
2
3
P (0.05 mmol), and PEG-6000 (1 g) in
b
c
3
)
d
(0.05 mmol) and (2-furyl)
3
P (0.2 mmol). Determined by GC.
3
acetate 2b was because of a rapid σ↔η ↔σ transformation of the
intermediates compared to the rate of allylation. The reaction with
longer linear carbon allyl acetate, trans hexen-1-yl acetate (2d) gave
The desired N1-selective outcomes of the reaction conditions
evaluated above were found to apply to various substituted indoles
in Table 5. Initially, allylation of the simpler, monosubstituted, 3-
methylindoles was under investigation. The N-allylated yield was
2% (3f). Then, allylation of diverse steric and electronic properties
were reacted smoothly to give N1-allylated products in good to
3
c and 4c in 77% and 3% yields, respectively (entry 3). On the other
hand, the allyaltion with branched isomer, hex-1-en-3-yl acetate (2e)
got prominent N-allylated product (3c) in 81% yield (entry 4). The
allylation of 2-methylallyl acetate (2f) produced a 74% yield on 3d
8
excellent yields. Variation with other indoles and allyl acetate using
(entry 5). However, the reaction process seemed to be hard to the 3-
This journal is © The Royal Society of Chemistry 20xx
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this one-pot process led to the synthesis of the corresponding N-
allylic indoles in high yields from 96% to 98% yield (3g–j).
Conclusions
View Article Online
DOI: 10.1039/C9NJ02335F
In summary, we have developed a general method for
establishing C-N bond formation on heterocyclic fused indoles in
PEG-6000. This system provides a simple, convenient, efficient and
environmentally-friendly way to achieve N-selective allylation in
water. The N-allylation of complex indole substrates in the green
solvent is enlightened by the current work. In addition, the allylation
of allylic acetates worked well with indoles, giving useful yields of the
corresponding allylic indoles.
Table 5. Scope of the N1-selective allylation of indoles with allyl
acetate (2).
allyl acetate (2 mmol)
Pd(OCOCF ) (0.025 mmol)
3
2
(
2-furyl) P (0.05 mmol)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
N-allylated
indoles
a
indoles 3, yield
1
PEG-6000 (1 g)
o
H O, 100 C, 2-3 h
2
Conflicts of interest
N
N
N
There are no conflicts to declare.
3
f 82b
3g 97
3h 98
Acknowledgements
This work was supported by a grant from the National Science
Council of Republic of China (NSC101-2113-M-037-008-MY3)
N
N
3
i 97
3j 96
Notes and references
a
b
Isolated yield. Refluxed 3 h.
1
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(
indoles is illustrated in Scheme 3. We envision that PEG serves as a
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HOAc
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Scheme 3. Proposed mechanism.
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View Article Online
DOI: 10.1039/C9NJ02335F
Table of contents entry
Palladium-Catalyzed Selective N-Allylation of Indoles assisted by
PEG-Water System
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ab
a
b
c
acd
Bai-Jing Peng , Wen-Ting Hsueh , Ferenc Fülöp , I-Ling Lin and Shyh-Chyun Yang *
R
R2
OAc
R2
R3
R3
1
.N1 selective allylation
2
a
R1
2.Yields up to 98%
R1
N
N
3.Reacted in two hours
Pd catalyst, Ligand
H
4
.Water as solvent
PEG, H O
2
2a
R