Palladium-catalyzed cyclization reaction of N-(2-Haloaryl)alkynylimines: Synthesis of 3-acylindoles using water as the sole solvent and oxygen source

Article abstract of DOI:10.1002/aoc.5513

A simple and efficient strategy for the preparation of 3-acylindoles via palladium-catalyzed cyclization reaction of N-(2-haloaryl)alkynylimines in water has been developed. The reaction tolerates a wide range of functional groups, and the corresponding 3-acylindoles were obtained in high yields using water as the sole solvent and oxygen sources. Additionally, this method could provide a short synthesis route for Pravadoline, a phase II analgesic drug.

Full text of DOI:10.1002/aoc.5513

Received: 18 November 2019
DOI: 10.1002/aoc.5513
Revised: 26 December 2019
Accepted: 5 January 2020
F U L L P A P E R
Palladium-catalyzed cyclization reaction of N-(2-Haloaryl)
alkynylimines: Synthesis of 3-acylindoles using water as the
sole solvent and oxygen source
An-An Zhang1 | Tuanjie Meng1 | Wenli Wang1 | Xueli Liu1 | Yupei Zhu1
Lantao Liu1,2,3
|
1College of Chemistry and Chemical
A simple and efficient strategy for the preparation of 3-acylindoles via palla-
dium-catalyzed cyclization reaction of N-(2-haloaryl)alkynylimines in water
has been developed. The reaction tolerates a wide range of functional groups,
and the corresponding 3-acylindoles were obtained in high yields using water
as the sole solvent and oxygen sources. Additionally, this method could pro-
vide a short synthesis route for Pravadoline, a phase II analgesic drug.
Engineering, Shangqiu Normal
University, Shangqiu, 47600, P. R. China
2College of Chemistry, Zhengzhou
University, Zhengzhou, 450001, P. R.
China
3Beijing National Laboratory for
Molecular Sciences (BNLMS), College of
Chemistry, Peking University, Beijing,
100871, P. R. China
K E Y W O R D S
3-acylindoles, N-(2-haloaryl)alkynylimines, palladium-catalyzed cyclization, water
Correspondence
Lantao Liu, College of Chemistry and
Chemical Engineering, Shangqiu Normal
University, 298 Wenhua Road, Shangqiu,
Henan 476000, China.
Email: liult05@iccas.ac.cn
Funding information
National Natural Science Foundation of
China, Grant/Award Number: 21572126,
21202095, 21172139, 21271125; Program
for Science & Technology Innovation
Talents in Universities of Henan Province,
Grant/Award Number: 14HASTIT016;
Program of Science and Technology
Innovation Talents of Henan Province,
Grant/Award Number: 2018JQ0011
1 | INTRODUCTION
acylindoles. In the past few years, the direct 3-acylation
of indoles has been developed, and is well synthetic pro-
Acylated indoles are ubiquitous in biologically active nat-
ural products and pharmaceutical compounds, and are
also versatile precursors for the synthesis of alkaloids and
other related heterocycles. In particular, 3-acylindoles are
frequently reported as important leading compounds
with diverse pharmacological effects, such as analgesic,
cedures of 3-acylindoles.[2] On the other hand, direct con-
struction of the 3-acylindole skeleton from acyclic
precursors has also got considerable attention, and some
significant approaches have been achieved, such as intra-
molecular cyclization of enaminones,[3] direct intramo-
lecular oxidative coupling or radical cyclization of
aminoalkynes,[4] Rh-catalyzed annulation of N-
phenylamidines with α-Cl ketones,[5] Ru- or Rh-catalyzed
selective C-H activation/annulation of imidamides and
tubulin
polymerization
inhibitor,
and
hypocholesterolemic activities. (Figure 1)[1] Conse-
quently, much effort has focused on the synthesis of 3-
Appl Organometal Chem. 2020;e5513.
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© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5513

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ZHANG ET AL.
FIGURE 1 Selected
examples of bioactive 3-
acylindoles
TABLE 1 Optimization of reaction conditionsa
Entry
1
[Pd]
base
L
addtive
--
t [ꢀC]
110
110
110
110
110
110
110
100
120
120
120
120
120
120
120
120
120
120
yield (%)b
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
PdCl2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KOAc
PPh3
--
80
2
TBAB
TBAB
TBAB
TBAB
TBAI
TBAC
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
trace
96
3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PCy3
BINAP
PPh3
PPh3
PPh3
PPh3
4
87
5
Pd (dba)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
88
6
93
7
83
8
76
9
99
10
11
12
13
14
15c
16d
17e
18f
97
67
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
89
22
trace
92
99 (98)
92
84
aReaction conditions: 1a (0.20 mmol), in the 4 ml H2O, at the indicated temperature under an argon atmosphere.
bYields of 2a were measured by 1H NMR with dibromomethane as the internal standard. Isolated yield is in parentheses.
cCs2CO3 (1.5 equiv).
dPd (OAc)2 (5 mol %), PPh3 (10 mol %).
eUsing 2 ml toluene and 2.5 equiv H2O as the solvent.
fUsing 2 ml toluene and 10.0 equiv H2O as the solvent.

SYNTHESIS OF 3-ACYLINDOLES USING WATER AS THE SOLE SOLVENT
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sulfoxonium ylides,[6] iodine-mediated tandem aza-
michael addition/C-H functionalization of aniline and
α,β-ynones,[7] copper-catalyzed cyclization of N-(2-
intramolecular radical cyclization of N-[2-(alkynyl)phe-
nyl]trifluoroacetimidoyl
isocyanide insertion and oxypalladation of alkyne,[10] vis-
ible-light-induced oxidant and metal-free
chlorides,[9]
Pd-catalyzed
iodoaryl)enaminones,[8]
visible
light
induced
TABLE 2 Substrate scopea,b
aReaction conditions: 1 (0.2 mmol), Pd (OAc)2 (5.0 mol %), PPh3 (10.0 mol %), Cs2CO3 (3.0 equiv.), TBAB (50.0 mol %) and H2O (4.0 ml), at 120 ꢀC for 12 hr
under an argon atmosphere.
bIsolated yield.

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ZHANG ET AL.
dehydrogenative cascade trifluoromethylation and oxida-
tion of 1,6-enynes with water,[11] as well as palladium-
catalyzed cyclization reaction of N-(o-haloaryl)
alkynylimines producing 2-trifluoromethylindole deriva-
tives.[12] From the perspective of green chemistry, water
is an ideal solvent since it is a non-toxic, abundant, cost-
effective and environmental-friendly solvent.[13] Water as
the sole solvent and oxygen sources represents one of the
best strategies for green chemistry. Herein, we report a
simple strategy for the preparation of 3-acylindoles via
palladium-catalyzed cyclization reaction of N-(2-haloaryl)
alkynylimines using water as the sole solvent and oxygen
sources and its application in concise synthesis of
Pravadoline, a phase II analgesic drug.
results showed that the use of Pd (OAc)2 and TBAB gave
best yield of the product (Table 1, entries 3–7). To
improve the yield, the temperaturꢀe was examined,
resulting in the optimal one at 120 C (Table 1, entry
3, entries 8–9). Among the bases and ligands studied,
Cs2CO3 and PPh3 provided the best result (Table 1,
entries 9–14). Lowering the amount of the catalyst did
not significantly influence the yields (Table 1, entry 16).
We then probed the solvent effect and found that water
as the sole solvent was superior to a mixed solvent of tol-
uene and a small amount of water (Table 1, entries16–
18). The conditions used in entry 16 were therefore the
best for this reaction.
The substrate scope was investigated under the opti-
mized conditions and the results are summarized in
Table 2. A variety of N-(2-haloaryl)alkynylimine sub-
strates, containing electronically or different substitu-
ents, were converted into the corresponding products in
good to excellent yield. The effect of R1 groups was first
studied. In general, the desired products were obtained
with decent yields regardless of electric effects of R1
(Table 2, 2a-2h, 2x). However, the substrate with elec-
tron-withdrawing group such as 4-chlorophenyl gave the
product 2 h in slightly lower yield. The sterically hin-
dered substrate bearing 2-methylphenyl group gave the
product 2c in relatively lower, but pretty good, yield. It
is worth noting that product 2 g with thiophen-2-yl
2 | RESULTS AND DISCUSSION
Initially, our initial efforts focused on optimization of the
reaction conditions, using (Z)-2-bromo-N-(1-phenyl-3-(p-
tolyl)prop-2-yn-1-ylidene)aniline (1a) as a model sub-
strate (Table 1). Treatment of 1a with 10 mol% Pd
(OAc)2, 20 mol% PPh3 and 3 equiv of Cs2CO3 in H2O at
110 ꢀC under argon atmosphere gave the 3-acylindoles 2a
in 80% yield (Table 1, entry 1). The addition of 50 mol%
of TBAB accelerated the reaction and increased the yield
of 2a to 96% (Table 1, entry 3). Next, different palladium
sources and additives were screened, and preliminary
SCHEME 1 Gram-scale preparation
SCHEME 3 Mechanistic studies
SCHEME 2 Conversion of the product

SYNTHESIS OF 3-ACYLINDOLES USING WATER AS THE SOLE SOLVENT
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SCHEME 4 Proposed reaction
mechanism
group was generated in excellent yield and the alkyl
substituted substrate 1x was converted into the
corresponding product 2x in 77% of isolated yield. Then
the substrates with different R2 groups were then
checked (Table 2, 2i-2p). The excellent yields of products
2i-2 k, with methyl group at different positions of R2,
indicated that the steric effect of R2 has no obvious influ-
ence on the yield. N-(2-Haloaryl)alkynylimine bearing
electron-withdrawing groups produced products 2 m and
2n in satisfactory, but slightly lower, yields. In addition,
thiophen-2-yl group was also tolerated here generating
2o in 91% of isolated yield. Finally the substrates with
different R3 groups were also suitable for the reaction
affording the corresponding products 2p-2v successfully
in good to excellent yields.
Furthermore, the potential application of this method
was illustrated by gram-scale synthesis. Under the stan-
dard conditions, the desired 3-acylindoles product 2i was
obtained with a yield of 81% when the reaction was car-
ried out at a 2.8 mmol scale (Scheme 1). Significantly,
our protocol could provide a short synthesis route for
Pravadoline, a phase II drug, which was recognized as a
cannabinoid CB1 receptor agonist with a strong analgesic
effect (IC50 = 4.9 μM).1h Its synthetic protocol was pro-
vided in Scheme 2. Firstly, a concise synthesis of 1w was
achieved by one-pot two steps reactions from N-(2-
bromophenyl)acetamide which was then converted to 2-
methyl-3-acylindoles 2w in 65% total yield without isola-
tion. Finally, Pravadoline was obtained in easily in 54%
isolated yield.
On the basis of our results and previous reports,[10,12]
a plausible mechanistic pathway for the formation of 2a
is depicted in Scheme 4. Initially, oxidative addition of
Pd(0) to aryl halide generates arylpalladium bromide
A. Under the activation of arylpalladium, the oxy-
palladation of the internal alkyne with H2O, takes place
to give the six-membered palladacycle B. C-C reductive
elimination regenerates the Pd(0) species and affords
compound C, which isomerizes to the desired product D.
3 | CONCLUSIONS
In conclusion, we have developed an efficient strategy for
the synthesis of biologically important 3-acylindoles from
the N-(2-haloaryl)alkynylimines in water. Notably, the
solvent of this cyclization reaction is water, which repre-
sents a low-cost, environmentally friendly and sustain-
able medium. The method shows remarkable features,
including extensive substrate compatibility and gram-
scale synthesis. In addition, a concise synthesis of
Pravadoline, a phase II drug demonstrate the synthetic
utility of this protocol.
4 | EXPERIMENTAL SECTION
4.1 | General procedure for the synthesis
of 3-acylindoles
We also performed labeling experiments to identify
the oxygen source in product 2a (Scheme 3). The 18O
incorporated product 2a-18O was formed with H218O as
the solvent, and the ratio of 2a-18O:2a was 93:7. It is indi-
cated that the carbonyl oxygen originated from H2O.
A 10 ml Schlenk-type sealed tube was charged with N-(2-
haloaryl)alkynylimines (0.2 mmol), Pd (OAc)2 (2.3 mg,
0.01 mmol, 5.0 mol %), PPh3 (5.3 mg, 0.02 mmol,
10.0 mol %), Cs2CO3 (195.5 mg, 0.6 mmol, 3.0 equiv.),
TBAB (32.2 mg, 0.1 mmol, 50.0 mol %) and H2O (4.0 ml).

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ZHANG ET AL.
The reaction mixture was stirred at 120 ꢀC for 12 hr
under an argon atmosphere. After the reaction was com-
plete, then cooled to the room temperature. The reaction
mixture was extracted with ethyl acetate three times. The
combined extracts were washed with brine, dried over
Na2SO4 and concentrated under reduced pressure, the
residue was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 1/1, v/v) to afford the
desired 3-acylindoles (data of 3-acylindoles see details in
the Supporting Information).
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ACKNOWLEDGMENTS
This work was supported by the National Natural
Science Foundation of China (Nos. 21572126, 21202095,
21172139, 21271125), Program of Science and Technology
Innovation Talents of Henan Province (2018JQ0011),
and the Program for Science & Technology Innovation
Talents
in
Universities
of
Henan
Province
(14HASTIT016).
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How to cite this article: Zhang A-A, Meng T,
Wang W, Liu X, Zhu Y, Liu L. Palladium-catalyzed
cyclization reaction of N-(2-Haloaryl)
alkynylimines: Synthesis of 3-acylindoles using
water as the sole solvent and oxygen source. Appl
Organometal Chem. 2020;e5513. https://doi.org/10.
1002/aoc.5513
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.