Palladium-catalyzed three-component synthesis of 3-(diarylmethylene) oxindoles through a domino sonagashira/carbopalladation/C-H activation/C-C bond-forming sequence

Article abstract of DOI:10.1002/anie.200605192

(Chemical Equation Presented) 3-3-1 Formation: [Pd(PPh₃) ₄]/Cul serves as an efficient catalyst for the reaction of three readily available starting materials to give 3-(diarylmethylene)indolin-2-ones 3 through a sequence of intermol

Full text of DOI:10.1002/anie.200605192

Angewandte
Chemie
DOI: 10.1002/anie.200605192
Domino Reactions
Palladium-Catalyzed Three-Component Synthesis of
3
-(Diarylmethylene)oxindoles through a Domino Sonagashira/
À
À
Carbopalladation/C H Activation/C C Bond-Forming Sequence**
Artur Pinto, Luc Neuville, and Jieping Zhu*
Devising novel multicomponent reactions (MCRs) that
achieve the formation of multiple bonds in one operation is
[
1]
one of the major challenges in modern organic synthesis. As
such processes avoid time-consuming and costly purification
processes, as well as protection–deprotection steps, they are
[
2]
inherently environmentally benign and atom economic.
[
3]
Whereas some powerful MCRs such as the Passerini and
[
4]
Ugi reactions proceed in the absence of external reagents,
most chemical transformations involve reactants that are not
active enough to be self-assembled. Thus, the use of catalytic
rather than stoichiometric amounts of external reagents to
trigger the reaction is highly desirable to minimize the
[
5]
production of waste. As a continuation of our ongoing
project on the development of palladium-catalyzed domino
Scheme 1. Proposed three-component reaction to synthesize 3-(diaryl-
methylene)oxindoles.
[
6]
[7]
processes as well as direct CÀH functionalization, we
report herein a palladium-catalyzed three-component syn-
[
8–13]
thesis of 3-(diarylmethylene)indolinones.
principle of our approach is shown in Scheme 1. The
Sonogashira coupling
The underlying
ladation, and direct CÀH functionalization, has not been
[
14]
[20]
of N-aryl-N-alkyl propiolamides 1
reported previously.
with an aryl iodide 2 should give the phenyl propiolamide 5,
which would then react with a second aryl halide 3, ideally in
the presence of the same catalyst, to afford the target
compound 4 through a sequence of intermolecular carbopal-
ladation, CÀH activation, and a CÀC bond-forming pro-
Very few examples have been reported that deal with the
successful Sonogashira reaction of electron-deficient alkynes,
[
21]
[22]
such as propiolic esters
and propiolamide,
with aryl
halides. Despite this potential pitfall, we performed a survey
of reaction conditions using N-(4-methoxyphenyl)-N-methyl
propiolamide (1a), phenyl iodide (2a), and 2-nitrophenylio-
dide (3a) as test substrates. In the event, stirring a solution of
1a and 2a in N,N-dimethylformamide (DMF) in the presence
of [Pd(PPh ) ] (5 mol%), copper iodide (15 mol%), and Et N
[
15,16]
cess.
Whereas many palladium-catalyzed transformations
have been developed and widely used in novel domino
[
17,18]
processes for the syntheses of heterocycles,
the MCR that
combines mechanistically distinct reactions by a single
catalyst is by far less developed owing to the specificity of
3
4
3
at 608C for 1 h followed by addition of 3a and heating to
1108C for 15 h afforded the expected oxindole 4a in 28%
yield. Control experiments indicated that a) Sonogashira
coupling between 1a and 2a, the presumed first step of this
domino process, proceeded smoothly to furnish the phenyl-
propiolamide 5a in over 90% yield, b) copper iodide is
required for the successful Sonogashira coupling between 1a
[
19]
each catalytic system to each individual reaction. To our
knowledge, the use of a single palladium catalyst to catalyze
three different reactions, namely aryl alkynylation, carbopal-
[*] A. Pinto, Dr. L. Neuville, Dr. J. Zhu
[
23]
and 2a, and c) the Sonogashira coupling between 1a and 2a
proceeded sluggishly under ligand-free conditions, although
such conditions were of choice for the carbopalladation/CÀH
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-Yvette Cedex (France)
Fax: (+33)1-6907-7247
E-mail: zhu@icsn.cnrs-gif.fr
Homepage: http://www.icsn.cnrs-gif.fr/article.php3?id_
article=122
functionalization step. With these results in hand, we set out
to focus on the overall reaction efficiency of this novel three-
component reaction instead of optimizing the individual
[
**] Financialsupport from the CNRS and the Institut de Chimie des
Substances Naturelles, CNRS, is gratefully acknowledged. A.P.
thanks the “Minist›re de l’Enseignement SupØrieur et de la
Recherche” for a doctoral fellowship.
[24]
steps
by varying the palladium source, the ligand, the
amount of copper, the base, and the solvent. The results are
summarized in Table 1.
The base played an important role in the overall efficiency
of this three-component reaction. Simply by switching from
triethylamine to sodium acetate under otherwise identical
conditions furnished the desired oxindole 4a in 73% yield.
Supporting information for this article, including experimental
procedures, product characterization, as well as copies of H NMR
spectra of oxindoles 4a–4s, is available on the WWW under http://
www.angewandte.org or from the author.
1
Angew. Chem. Int. Ed. 2007, 46, 3291 –3295
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3291

Communications
[
a]
Table 1: Palladium-catalyzed three-component synthesis of oxindoles: a survey of reaction conditions.
Entry
[Pd] (mol%)
CuI [mol%]
Base (equiv)
So lv ent
t ,t [h]
Yield [%]
1
2
4
a
5a
4b
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
[Pd(PPh ) ] (5)
15
15
15
15
15
15
15
15
5
5
5
5
5
Et N (2)
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
Dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
1, 15
4, 45
4, 17
4, 3
28
73
58
48
58
53
52
–
–
11
–
–
–
5
46
n.d.
6
13
7
–
3
6
3
10
8
–
–
79
–
11
3
3
4
3
[Pd(PPh ) ] (5)
NaOAc (2)
NaOAc (2)
NaOAc (2)
NaOAc (2)
NaOAc (2)
NaOAc (2)
NaOAc (2)
NaOAc (2)
KOAc (2)
3
4
Pd(OAc) /PPh (5:10)
2
3
[Pd(PPh ) Cl ] (5)
3
2
2
[Pd(dba)]/PPh (5:10)
1, 13
1, 42
1, 42
17, 48
1, 39
1, 24
1, 28
1, 39
1, 26
1, 44
1, 24
3
[Pd(PPh ) ] (5)
3
4
[Pd(PPh ) ] (5)
3
4
[
b]
[Pd(PPh ) ] (5)
3
4
[
[
[
[
[
[
[
c]
c]
c]
c]
c]
c]
c]
[Pd(PPh ) ] (10)
–
3
4
1
1
1
1
1
1
[Pd(PPh ) ] (5)
79
66
63
63
82
77
3
4
[Pd(PPh ) ] (10)
K CO (2)
3
4
2
3
[Pd(PPh ) ] (10)
NaHCO (2)
6
5
–
6
3
4
3
[Pd(PPh ) ] (10)
K PO (2)
5
3
3
3
4
3
4
[Pd(PPh ) ] (10)
5
2.5
NaOAc (3)
NaOAc (3)
3
4
[Pd(PPh ) ] (5)
3
4
[a] All reactions were carried out under argon using 1a (1.0 equiv), 2a (1.0 equiv), Pd catalyst, base, and solvent (c=0.1m) at 608C for the indicated
time (t ); then, 3a (1.1 equiv) was added and the reaction mixture was heated at 1108C (t ). [b] Only compound 5a formed, but its yield was not
1
2
determined (n.d.). [c] 1.1 equiv 1a was used. dba=dibenzylideneacetone.
Other inorganic bases were examined, and NaOAc and
KOAc were found to be superior to NaHCO and K PO
only weakly influenced by the electronic properties of the aryl
halides, and a variety of oxindoles substituted by an electron-
donating or an electron-withdrawing group were readily
synthesized in good to excellent yields (Table 2, entries 1–5).
Whereas ortho-, meta-, and para-substituted aryl iodides can
be used as the second aryl iodide (Table 2, entries 1, 6, and 8),
only para- and meta-substituted aryl halides were well
tolerated when used as the first aryl iodide added. The
chlorine atom is compatible with this reaction sequence by
providing a handle for further functionalization (Table 2,
3
3
4
(
Table 1, entries 9–13), with three equivalents of NaOAc
being optimal (entry 14). Among the palladium catalysts
investigated (Table 1, entries 2–5), palladium
tetrakis(triphenylphosphine) was found to be the most
effective (entry 2). DMF proved to be a better solvent than
N,N-dimethylacetamide (DMA) or dimethyl sulfoxide
(
DMSO), while dioxane was inefficient in promoting the
second step (Table 1, entries 6–8). The presence of copper
iodide is essential to the Sonogashira coupling, but it retarded
the carbopalladation/CÀH functionalization process. The best
entries 4
and
8).
The
N-(2-trimethylsilylethoxy-
methoxy)anilide 3b participated in this three-component
reaction albeit the yield was slightly decreased (Table 2,
entry 8). As an N-SEM group is readily removed, it con-
stituted a route to N-unsubstituted oxindoles. Note that both
Pd/Cu ratio was found to be 2:1 (Table 1, entry 2 vs. 9).
Overall, under optimum conditions (5 mol% [Pd(PPh ) ],
3
4
2
.5 mol% CuI, 3 equiv NaOAc, DMF, c = 0.1m; Table 1,
entry 15), the reaction of 1a, 2a, and 3a provided the desired
oxindole 4a in 77% yield. Under these conditions, the
phenylpropiolamide 5a and the symmetrically substituted
oxindole 4b were also isolated in yields of 6% and 3%,
respectively.
To probe the scope and limitation of this new three-
component reaction, a range of substituted aryl iodides and
propiolamides were next examined (Scheme 2, Table 2). The
outcome of this three-component reaction was found to be
Scheme 3. Synthesis of symmetrically substituted 3-(diaryl-
Scheme 2. Anilides 1 used in Table 2.
methylene)oxindoles.
3
292
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Angewandte
Chemie
[
a]
Table 2: Scope of the palladium-catalyzed three-component synthesis of 3-(diarylmethylene)oxindoles. Structures of anilides 1 are given in Scheme 3.
1
2
[b]
1
2
[b]
Entry
1
Ar I
Ar I
Product
Yield [%]
Entry
1
Ar I
Ar I
Product
Yield [%]
67
1
1a
77
9
1c
2
3
4
5
1a
1a
1a
1a
82
71
76
78
10
11
12
13
1a
1a
1a
1a
<10
69
81
61
6
1a
66
14
1a
45
7
8
1a
1b
43
59
15
16
1a
1a
0
51
1
2
[
a] Generalconditions: 1a (1.1 equiv), Ar I (1.0 equiv), CuI (2.5 mol%), [Pd(PPh ) ] (5 mol%), NaOAc (3 equiv), DMF (c=0.1m), 608C; then Ar I (1.1 equiv),
3
4
1
108C. [b] Yield of product isolated after flash column chromatography.
the E- and the Z-oxindole can be prepared from the same
starting materials by simply changing the order of addition of
the two aryl halides (Table 2, entries 6 and 7).
To further exploit the generality of this catalytic MCR and
because of the biological relevancy of heterocycles, we
investigated the possibility of incorporating heteroaryl
groups into the target compounds. As is seen from Table 2
(entries 11–16), 3-iodopyridine, 5-iodoindole, and 2-iodothio-
phene were appropriate starting materials for this MCR.
Whereas 3-iodopyridine was a suitable reactant for both the
Sonogashira coupling and the carbopalladation step, leading
to compound 4l and 4m, respectively, 2-iodopyridine could
only be used as a reaction partner in the Sonogashira coupling
1
(Ar I). When it was used for the carbapalladation/direct CÀH
Angew. Chem. Int. Ed. 2007, 46, 3291 –3295
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3293

Communications
1
functionalization sequence (Ar I), the expected oxindole 4p
Bulger, Angew. Chem. 2006, 118, 7292 – 7344; Angew. Chem. Int.
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pyridine is able to sequester the Pd species by forming a five-
membered chelate after the carbopalladation step, thereby
II
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4
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oxindole 4n in 61% yield (Table 2, entry 13). Finally, a
symmetrically substituted oxindole, 4r, was synthesized in
1
5
7% yield by simply conducting the reaction with two
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In summary, we have developed a flexible and stereocon-
trolled three-component synthesis of unsymmetrically sub-
stituted 3-(diarylmethylene)indolinones. The overall reaction
involves a sequence of Sonogashira reaction/carbopallada-
tion/CÀH activation, and CÀC bond formation and is
1
8
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[
Pd(Ph ) ] (5 mol%) were added to a degassed solution of anilide
3 4
(1.1 equiv) and aryl iodide (1.0 equiv) in DMF (c = 0.1m). The
6
mixture was heated at 608C for 1 h, and then the second aryl iodide
1.1 equiv) was introduced. After being stirred at 1108C for 28 h, the
[
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(
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4
was purified by flash chromatography to give the corresponding
oxindole.
(
3E)-5-methoxy-1-methyl-3-[(2-nitrophenyl)(phenyl)meth-
2
ylene]-1,3-dihydro-2H-indol-2-one (4a): 72 mg (77% yield); red
1
solid; m.p. 197–2008C; H NMR (300 MHz, CDCl ): d = 8.19 (dd,
3
3
J = 8.2, 1.1 Hz, 1H), 7.77 (dt, J = 7.5, 1.1 Hz, 1H), 7.65 (dt, J = 8.2,
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1
7
5
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1
3
.60 (d, J = 2.4 Hz, 1H), 3.48 (s, 3H), 3.17 ppm (s, 3H); C NMR
(
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3
18
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Received: December 22, 2006
Published online: March 22, 2007
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294 www.angewandte.org
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Angew. Chem. Int. Ed. 2007, 46, 3291 –3295

Angewandte
Chemie
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