A general and convenient palladium-catalyzed synthesis of benzylideneindolin-3-ones with formic acid as the CO source

Article abstract of DOI:10.1039/c7ob01557g

A general and convenient palladium-catalyzed carbonylative synthesis of 2-benzylideneindolin-3-ones from 2-iodoanilines and arylacetylenes has been developed. With formic acid as the CO source and Ac₂O as the activator, a variety of 2-benzylideneindolin-3-ones were obtained in good to excellent yields with exceptional functional group tolerance.

Full text of DOI:10.1039/c7ob01557g

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A General and Convenient Palladium-Catalyzed Synthesis of
Benzylideneindolin-3-ones with Formic Acid as the CO Source
Rui Li, a Xinxin Qi,a Xiao-Feng Wu*,a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
general and convenient palladium-catalyzed carbonylative palladium-catalyzed carbonylation reaction of 2-iodoaniline and
synthesis of 2-benzylideneindolin-3-ones from 2-iodoanilines and acetylenes to produce the 2-benzylidene-indolin-3-ones with formic
arylacetylenes has been developed. With formic acid as the CO acid as the CO precursor.[16]
source and Ac2O as the activator,
a
variety of 2- 2-Iodoaniline and phenyl acetylene were used as initial substrates,
benzylideneindolin-3-ones were obtained in good to excellent with Pd(PPh3)4 as catalyst and Et3N as base in toluene at 70 °C for
yields with exceptional functional groups tolerance.
14 h (Table 1, entry 1), to our delight, the desired product was
obtained in 52% yield. Then we tested Pd(OAc)2 and PdCl2(PPh3)2
with PPh3 as the ligand, yields of the desired products decreased to
15% and 5% respectively (Table 1, entries 2-3). Then a variety of
ligands such as DPPP, DPPF, Xphos, BINAP, BuPAd2, and PCy3 were
examined, low yields were observed in these cases (Table 1, entries
4-9). The yields cannot be improved in the bases variation (Table 1,
entries 10-13) and solvents screening (Table 1, entries 14-17).
During the optimization process, N-(2-iodophenyl)acetamide and N-
phenylacetamide are the most common byproducts observed
together with starting materials. Then we believe that the results
might be improved by stirring the reaction mixture at room
temperature for a while to facility the formic acid activation via
acetic formic anhydride formation. Delightly, 81% yield of the
desired product was obtained by conducting the reaction at room
temperature for 2 h and then 70 °C for 14 h (Table 1, entry 18). In
the absence of Ac2O, no desired product can be detected but
Indolin-3-ones represent an important class of structural units that
frequently present in many natural products, biologically active
molecules, and pharmaceutical compounds.[1] They have found
wide applications in medicine[2] and polymers.[3] Due to their unique
bioactivities, a lot of interests have been attracted from synthetic
chemists. However, compare with indolin-2-ones, the synthetic
methods for indolin-3-ones are still limited. Traditional synthetic
strategies for indolin-3-ones mainly rely on oxidation of existing
indoles,[4] condensation of o-nitrobenzaldehydes with cyclic
ketones,[5] base or acid promoted cyclization,[6] and so on. In recent
years, transition-metal catalyzed cycloisomerization has been
regarded as one of the most efficient method to construct
carbocycles,[7] and Ag,[8] Al,[9] Au,[10] Pd,[11] Ru[12] has been explored
in the synthesis of indolin-3-ones.
On the other hand, palladium-catalyzed carbonylation reaction has
attracted continuous attention for their widely applications in both
academic and industrial fields.[13] Catellani’s group developed a
palladium-catalyzed carbonylative reaction for the synthesis of 2-
arylmethylidene-indoxyls under CO atmosphere in 1990 with two
examples given.[14] Later on, Djakovitch, Dufaud and their co-
workers studied this transformation in more detail and reported a
heterogeneous palladium catalyzed model study on 2-iodoaniline
and phenylacetylene under CO pressure (5 bar) as well.[15] However,
due to the toxicity, odorless and high flammable properties of CO
gas, the development of new CO-free procedure is highly under
demand. Herein, we wish to disclose a general and convenient
starting
materials,
N-(2-iodophenyl)acetamide
and
N-
phenylacetamide.
Table 1. Screening of reaction conditions.[a]
Yield
Entry
Catalyst
Ligand
Base
Solvent
(%)[b]
52
15
5
1
2
3
4
5
6
7
8
Pd(PPh3)4
PdCl2(PPh3)2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
PPh3
PPh3
DPPP
DPPF
Xphos
BINAP
BuPAd2
10
24
38
33
23
a.Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus,
Hangzhou 310018, People’s Republic of China. E-mail: xiao-feng.wu@catalysis.de
b.Leibniz-Institut für Katalyse e.V. an der Universit Rostock, Albert-Einstein-Strasse
29a, 18059 Rostock, Germany
Electronic Supplementary Information (ESI) available: [experiment detail]. See
DOI: 10.1039/x0xx00000x
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9
10
11
12
13
14
15
16
17
18[c]
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PCy3
Et3N
NaOH
DIPEA
DBU
K2CO3
Et3N
Et3N
Et3N
Et3N
Et3N
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
THF
CH2Cl2
1,4-dioxane
Toluene
35
32
31
28
35
0
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DOI: 10.1039/C7OB01557G
5
73
2e
3e
0
6
7
76
20
37
81
2f
3f
[a] Reaction conditions: 2-iodoaniline (1.0 mmol), phenyl acetylene
(1.0 mmol), catalyst (3 mol%), ligand (6 mol%), base (6 equiv.),
HCOOH (2.0 mmol), acetic anhydride (2.0 mmol), solvent (2 mL), 70
°C, 14 h. [b] GC yield with dodecane as the internal standard. [c]
Catalyst (5 mol%), rt (2h)-70 °C (14h).
67
2g
3g
8
9
69
With the optimal reaction conditions in hand, we next investigated
a number of acetylenes, the results were summarized in Table 2.
Phenylacetylenes with electron-donating groups including methoxy,
tert-butyl, propyl, and methyl groups gave the corresponding
products in very good yields (Table 2, entries 2-7). Those substrates
with methyl group substituted at ortho-position provided lower
yield than meta- and para- substitution, probably due to the steric
hindrance (Table 2, entry 5, 6 vs. 7). Electron-withdrawing group
such as trifluoromethyl gave the desired products in 69% yield
(Table 2, entry 8). Furthermore, the examination of halogen groups
showed that fluoro group gives higher yield than chloro and bromo
groups (Table 2, entry 9 vs. 10, 11). Moreover, heteroaryl groups
involved thiophene and pyridine moieties could also smoothly
afford the target products in good yields (Table 2, entries 12-13).
2h
3h
80
2i
2j
3i
10
11
63
3j
58
2k
3k
Table 2. Palladium-catalyzed synthesis of benzylideneindolin-3-ones:
Reaction scope of acetylenes.[a]
12
13
59
2l
3l
Entry
1
Acetylenes
2a
Products
Yield (%)[b]
81
63
2m
3m
[a] Reaction conditions: 2-iodoanilines (1.0 mmol), acetylenes
(1.0 mmol), Pd(PPh3)4 (5 mol%), Et3N (6 equiv), HCOOH (2.0
mmol), acetic anhydride (2.0 mmol), toluene (2 mL), rt (2 h)-70
°C (14-18 h). [b] Isolated yield.
3a
2
3
4
61
72
74
We continued our study on the scope of 2-iodoanilines with
phenylacetylene (Table 3). Halogen groups substituted at para-
position to iodo group, including fluoro, chloro, and bromo groups
worked well to give the corresponding products in moderate yields
(Table 3, entries 1-4). Methoxy and methyl substituted products can
be isolated in 54-64% yields from the corresponding substrates as
well (Table 3, entries 5 and 6). And electron-withdrawing groups
can also be well tolerated and provided the desired products in a
good yields (Table 3, entries 7 and 8). Moreover, N-substitution,
including methyl and benzyl were investigated as well; the target
products were obtained in 56% and 69% yields, respectively (Table
3, entries 9-10).
2b
3b
2c
3c
2d
3d
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Table 3. Palladium-catalyzed synthesis of benzylideneindolin-3-ones:
Reaction scope of 2-iodoanilines.[a]
Yield
Entry
1
2-Iodoanilines
Products
(%)[b]
58
1b
1c
1d
1f
3n
Scheme 1. Proposed reaction mechanism.
2
3
4
5
6
7
52
42
67
54
64
68
3o
3p
3q
3r
In conclusion, a general and efficient strategy has been described to
prepare 2-benzylideneindolin-3-ones. In the presence of palladium
catalyst, 2-iodoanilines and arylacetylenes reacted successfully with
formic acid as the CO precursor. The desired 2-benzylideneindolin-
3-ones were obtained in good to high yields with exceptional
functional groups tolerance.
The authors thank the financial supports from NSFC (21472174,
21602201) and Zhejiang Natural Science Fund for
Distinguished Young Scholars (LR16B020002). X.-F. Wu
appreciates the general support from Professor Matthias
Beller in LIKAT.
1g
1k
1l
3s
Notes and references
General procedure: Pd(PPh3)4 (5 mol%, 58 mg), 2-iodoaniline (1.0
mmol, 219 mg), and phenylacetylene (1.0 mmol, 110 μL) were
transferred into an oven-dried tube which was filled with nitrogen
and equipped with a string bar. Toluene (2.0 mL), and Et3N (6.0
equiv., 6 mmol, 835 μL) were added into the reaction tube via
syringe. Then a mixture of formic acid (2.0 mmol, 76 μL) and acetic
anhydride (2.0 mmol, 189 μL) was stirred at 30°C for 1.5 h, and
added drop wise to the reaction tube. The final mixture was stirred
at room temperature for 2 h, and then raise to 70°C for another 14
h. After the reaction was complete, the reaction mixture was
filtered, concentrated, and purified by column chromatography on
silica gel (petroleum ether/ethyl acetate) to give the pure product.
3t
8
9
60
56
1m
3u
1n
3v
10
69
1o
3w
[a] Reaction conditions: 2-iodoanilines (1.0 mmol),
phenylacetylenes (1.0 mmol), Pd(PPh3)4 (5 mol%), Et3N (6
equiv.), HCOOH (2.0 mmol), acetic anhydride (2.0 mmol),
toluene (2 mL), rt (2 h)-70 °C (14-18 h). [b] Isolated yield.
1
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