Indium-mediated Palladium-catalyzed Allylic Alkylation of Isatins with Alkynes

Article abstract of DOI:10.1002/adsc.201701139

An unprecedented indium-mediated palladium-catalyzed allylic alkylation of isatins with alkynes is disclosed. This reaction provides a new, practical, and straightforward route to access 3-allyl-3-hydroxy-2-oxindoles in good yields with broad substrate scope and scalability, exhibiting high atom and step economy. A primary mechanistic study reveals that indium played two roles in the reaction, first as a reductant and second as a Lewis acid. Compared with previous methods, our strategy eliminated the steps for the separation and purification of the reaction intermediates, as well as pre-installing leaving groups to allylic substrates. Moreover, our reaction did not employ moisture-sensitive allylic metal species and stoichiometric oxidants. (Figure presented.).

Full text of DOI:10.1002/adsc.201701139

Title: Indium-mediated Palladium-catalyzed Allylic Alkylation of Isatins
with Alkynes
Authors: Zijun Wu , Xinxin Fang, Yuning Leng, Hequan Yao, and Aijun
Lin
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10.1002/adsc.201701139
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201
Indium-mediated Palladium-catalyzed Allylic Alkylation of
Isatins with Alkynes
Zijun Wu, Xinxin Fang, Yuning Leng, Hequan Yao,* and Aijun Lin*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy,
China Pharmaceutical University, Nanjing, 210009, P. R. China
Fax: (+86)-25-8327-1042; e-mail: ajlin@cpu.edu.cn and hyao@cpu.edu.cn
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
synthesize allylboronates[6] to realize allylation of
Abstract: An unprecedented indium-mediated palladium-
catalyzed allylic alkylation of isatins with alkynes is
disclosed. This reaction provides a new, practical, and
straightforward route to access 3-allyl-3-hydroxy-2-
oxindoles in good yields with broad substrate scope and
scalability, exhibiting high atom and step economy. A
primary mechanistic study reveals that indium played two
roles in the reaction, first as a reductant and second as a
Lewis acid. Compared with previous methods, our strategy
eliminated the steps for the separation and purification of
the reaction intermediates, as well as pre-installing leaving
groups to allylic substrates. Moreover, our reaction did not
employ moisture-sensitive allylic metal species and
stoichiometric oxidants.
isatins, while stoichiometric oxidants were required.
More recently, the transition-metal catalyzed allylation,
crotylation, and prenylation of isatins via isopropanol-
mediated transfer hydrogenation provided another
unique approach to synthesize 3-allyl-3-hydroxy-2-
oxindoles.[7] Again, this protocol suffered from
substrate scope limitations, especially with respect to
the allylic agents (Scheme 1d). Thus, exploiting new
methods to access 3-allyl-3-hydroxy-2-oxindoles from
readily available substrates with broad substrate scope
under mild conditions is still highly desirable.
Keywords: palladium-catalyzed; indium; 3-allyl-3-
hydroxy-2-oxindoles; isatins; allylic alkylation
3-Allyl-3-hydroxy-2-oxindoles as versatile building
blocks have been widely utilized for the preparation of
alkaloids, bioactive molecules, and clinical
pharmaceuticals.[1] Hydroxylation of 3-allyl-2-
oxindoles was one of the earliest reported methods to
prepare these skeletons (Scheme 1a).[2] However, the
preparation of 3-allyl-2-oxindoles under strong basic
conditions in low to moderate yields presented a strong
limitation. Wittig [2,3]-rearrangement as an alternative
method has also been reported to access such skeletons
(Scheme 1b).[3] Unfortunately, for the success of the
reaction, two or more steps are needed to pre-
synthesize
3-cinnamyloxyoxindoles,
involving
elaborate reaction routes and conditions. Allylation of
isatins with allylic metal species,[4,5] which could be
either pre-formed or formed in situ, has been the most
widely used method to obtain 3-allyl-3-hydroxy-2-
oxindoles (Scheme 1c). Nevertheless, the allylic metal
species are usually unstable and moisture sensitive,
making the reaction conditions difficult. Moreover, the
allylic reagents, such as allylic halides, esters, and
alcohols, which are mainly used to synthesize the
allylic metal species, need to be pre-prepared through
one or more extra steps. Transition-metal catalyzed
oxidative allylic C-H borylation could also be used to
Scheme 1. Strategies to the synthesis of 3-allyl-3-hydroxy-
2-oxindoles.
Alkynes, as versatile and readily available building
blocks,[8] have been employed in allylic alkylations[9]
and have drawn increasing interest from synthetic
chemists due to their inherent advantages for redox-
neutral processes. In conjunction with our ongoing
1
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10.1002/adsc.201701139
Advanced Synthesis & Catalysis
interest in exploring the reaction types of alkynes,[10] entries 2 and 3). Optimizing the solvents revealed that
herein, we describe our latest work on indium- toluene performed best and delivered 3aa in 89% yield
mediated palladium-catalyzed allylic alkylation of (Table 1, entries 4-7). Further screening of acids
isatins with alkynes to access 3-allyl-3-hydroxy-2- suggested that acetic acid is the best choice (Table 1,
oxindoles, featuring high atom and step economy, and entries 4 and 8-11). Decreasing the temperature
good functional group tolerance. Compared with resulted in low yield (Table 1, entry 12). Pd2(dba)3 or
previous methods, our strategy avoids steps for the Pd2(dba)3·CHCl3 with extra PPh3 could offer 3aa in
separation and purification of the reaction 73% and 68% yield (Table 1, entries 13 and 14).[11]
intermediates, as well as pre-functionalization of Further decreasing the catalyst loadings impacted the
allylic agents, which addressed the limitations of reaction efficiency (Table 1, entries 15-16). Control
previous synthetic methods.
experiments indicated that Pd(PPh3)4, indium and
acetic acid were all essential to this reaction (Table 1,
entries 17-19).
Table 1. Optimization of reaction conditions.[a, b]
Table 2. Substrate scope of alkynes.[a, b]
Entry Additive Acid
Solvent
Yield
1
2
3
4
5
6
7
8
In
Zn
Mn
In
In
In
In
In
In
In
In
In
In
In
In
In
In
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
PhCOOH
HCOOH
PivOH
THF
THF
THF
toluene
1,4-dioxane 71
DMF
DME
toluene
toluene
toluene
62
Trace
Trace
89
Trace
73
58
28
N.D.
Trace
54
73
68
77
61
N.D.
N.D.
N.D.
9
10
11
12[c]
13[d]
14[e]
15[f]
16[g]
17
18
19[h]
TsOH·H2O toluene
AcOH
AcOH
AcOH
AcOH
AcOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
AcOH
AcOH
In
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol),
Pd(PPh3)4 (10 mol%), In (0.4 mmol), acids (0.42 mmol)
o
in solvent (2.0 mL) were stirred at 90 C under argon
atmosphere for 8 h. DME = 1,2-dimethoxyethane. N.D.
= not detected.
[b]
[c]
[d]
[e]
[f]
Isolated yield.
70 oC.
Pd2(dba)3 (5.0 mol%), PPh3 (30 mol%)
Pd2(dba)3·CHCl3 (5.0 mol%), PPh3 (30 mol%)
Pd(PPh3)4 (7.5 mol%).
Pd(PPh3)4 (5.0 mol%).
Without Pd(PPh3)4.
[g]
[h]
[a]
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol),
Pd(PPh3)4 (10 mol%), In (0.4 mmol), AcOH (0.42
mmol) in toluene (2.0 mL) were stirred at 90 oC under
argon atmosphere for 8 h.
In order to identify an efficient catalyst system for
the synthesis of 3-allyl-3-hydroxy-2-oxindoles, we
focused our initial study on the reaction between N-
benzyl isatin 1a and 1-methoxy-4-(prop-1-yn-1-
yl)benzene 2a (Table 1). Gratifyingly, preliminary
attempts led to the desired product 3aa in 62% yield
when the reaction was treated with Pd(PPh3)4, indium
and acetic acid in tetrahydrofuran (THF) at 90 oC under
argon atmosphere (Table 1, entry 1). Other tested metal
additives (Zn and Mn) gave poor results (Table 1,
[b]
Isolated yields.
[c]
4.0 mmol scale.
100 oC
[d]
[e]
The dr value and the ratio of 2E/2Z were determined by
1H NMR spectra.
With the optimized conditions in hand, we then
examined the substrate scope of alkynes and the results
2
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10.1002/adsc.201701139
Advanced Synthesis & Catalysis
are summarized in Table 2. The alkynes with electron-
After checking the generality of alkynes, we then
donating or electron-withdrawing groups at the para- turned our attention to the substrate scope of isatins
position of the benzene ring provided 3aa-3ae in 76%- (Table 3). Isatins with various substituents at the 5-
89% yields. The steric hindrance of alkyne influenced position of the benzene ring provided 3ba-3ga in good
the reactivity and offered 3af in 63% yield, while meta- yields. The steric hindrance of isatins did not influence
methyl-substituted 2g afforded 3ag in 82% yield. the reactivity, offering 3ha and 3ia in 84% and 77%
Replacing the phenyl group with naphthyl, thienyl, yields. Delightedly, isatins with various groups on the
ferrocenyl and indolyl groups, the reaction proceeded N atom performed well, offering 3ja-3pa in 62%-93%
smoothly, leading to 3ai-3an in good yields. 1-Phenyl- yields.
1-butyne 2o participated well to deliver 3ao in 72%
yield (dr = 2:1). Moreover, pent-4-en-1-yn-1-
ylbenzene (2p), a skipped enyne, performed well,
offering 3ap in moderate yield. Aliphatic alkynes, e.g.
2q, were unreactive under the standard conditions.
Gram-scale experiment could also be carried out
conveniently and 3aa (1.35 g) was obtained in 88%
yield on 4.0 mmol scale.
Table 3. Substrate scope of isatins.[a, b]
Scheme 2. Transformation of products 3.
To illustrate the synthetic utility of this reaction,
further transformations of products 3 were conducted
(Scheme 2). Oxidation of the C=C double bond of 3aa
with osmium tetroxide and N-methyl-morpholine N-
oxide (NMO), followed by NaIO4, an unstable
aldehyde was formed, which could be used directly
without purification in the following step. Reduction of
the aldehyde with NaBH4 gave compound 4 in 70%
total yield within two steps. Compound 5 was obtained
in 95% yield through Pd/C catalytic hydrogenation.
Removing the N-acetyl group of 3pa could be readily
achieved with lithium hydroxide in MeOH at room
temperature, and compound 6 was obtained in 91%
yield.
Control experiments were then conducted to gain
insights into the mechanism of the reaction (Scheme
3a). When 1-benzyl-3-hydroxyindolin-2-one 7 reacted
with 1-methoxy-4-(prop-1-yn-1-yl)benzene 2a under
the standard conditions, 3aa was obtained in 82% yield
(Scheme 3a, eq 1). When the same reaction was carried
out in the absence of indium, 3aa was only obtained
in 41% yield (Scheme 3a, eq 2). These results
demonstrated that indium might play two roles in the
reaction, one is as a reductant and the other is as a
[a]
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol),
Lewis acid to promote the transformation. When
Pd(PPh3)4 (10 mol%), In (0.4 mmol), AcOH (0.42
benzaldehyde 8 was used as the substrate, no desired
mmol) in toluene (2.0 mL) were stirred at 90 oC under
compound 9 was detected (Scheme 3a, eq 3)[12, 13]. This
argon atmosphere for 8 h.
result suggests that the allylic indium species was not
[b]
Isolated yields.
formed in this reaction. Additionally, we prepared
phenyl allene 10 and cinnamyl acetate 11, and tested
[c]
100 oC.
them with 1a under the standard conditions; 3ac was
delivered in 51% and 55% yield, respectively (Scheme
3
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10.1002/adsc.201701139
Advanced Synthesis & Catalysis
3a, eq 4 and eq 5). These results indicate that phenyl and scalability, exhibiting high atom and step economy.
allene and cinnamyl acetate could be intermediates in The employment of alkynes as allyl equivalents in this
the reaction. [15]
reaction avoided pre-installing leaving groups to
On the basis of the above results and previous allylic substrates and employing moisture sensitive
work,[9,14] a plausible mechanism of our reaction is allylic metal species. Primary mechanism study
proposed as shown in Scheme 3b. First, oxidation of revealed that the indium played both as reductant and
Pd(PPh3)4 with acetic acid initials the catalytic cycles Lewis acid in this reaction. Further transformation of
and affords the hydridopalladium species A. syn- the products to functional compounds highlighted the
Migratory insertion of A to alkynes 2 delivers the potential application prospect of this reaction.
intermediate B. -Hydrogen elimination of B produces
the aryl allene C and regenerates A (cycle I). Next,
Experimental Section
migratory insertion of A to aryl allene C offers the key
π-allylpalladium species D,[15] which reacts with
intermediate E to give the allylic products 3 and
regenerates the palladium catalyst to the next catalytic
cycle (cycle II). On the other hand, it is thought that
with the help of indium, isatins could be reduced to
form compound 7, which coordinates with indium salt
to form intermediate E.
General procedure of allylation of isatins: A sealed tube
was charged with isatins 1 (0.2 mmol, 1.0 equiv), Pd(PPh3)4
(0.02 mmol, 10 mol%), indium (0.40 mmol, 2.0 equiv),
acetic acid (0.42 mmol, 2.1 equiv), alkynes 2 (0.4 mmol, 2.0
equiv) and toluene (2.0 mL). The reaction mixture was
o
vigorously stirred at 90 C (oil temperature) under argon
atmosphere for 8 h. After cooling to room temperature, the
reaction mixture was diluted with ethyl acetate (20 mL) and
filtered through a plug of Celite. The mixture was
concentrated in vacuo and purified by flash chromatography
on silica gel with PE/EA (v/v = 8:1 to 4:1) to afford the
allylic alkylated products 3.
Acknowledgements
Generous financial support from the National Natural Science
Foundation of China (NSFC21502232 and NSFC 21572272) is
gratefully acknowledged.
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In summary, we have developed an unprecedented
indium-mediated
palladium-catalyzed
allylic
alkylation of isatins with alkynes under mild reaction
conditions. This reaction provided a practical and
straightforward method to access 3-allyl-3-hydroxy-2-
oxindoles in good yields with broad substrate scope
4
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10.1002/adsc.201701139
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201701139
Advanced Synthesis & Catalysis
UPDATE
Indium-mediated Palladium-catalyzed Allylic
Alkylation of Isatins with Alkynes
Adv. Synth. Catal. Year, Volume, Page – Page
Zijun Wu, Xinxin Fang, Yuning Leng, Hequan
Yao,* and Aijun Lin*
6
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