An approach to spirooxindoles: Via palladium-catalyzed remote C-H activation and dual alkylation with CH2Br2

Article abstract of DOI:10.1039/c7cc06196j

A facile and efficient approach for the synthesis of spirooxindoles has been developed via the coupling of spirocyclic C,C-palladacycles with CH₂Br₂. The key spirocyclic palladacycles are generated catalytically via remote C-H activation. A range of spirooxindoles can be synthesized in good to excellent yields from readily available starting material.

Full text of DOI:10.1039/c7cc06196j

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An approach to spirooxindoles via palladium-
catalyzed remote C–H activation and dual
alkylation with CH2Br2†
Cite this: Chem. Commun., 2017,
53, 10429
Received 8th August 2017,
Accepted 3rd September 2017
Changdong Shao,
Zhuo Wu, Xiaoming Ji, Bo Zhou and Yanghui Zhang
*
DOI: 10.1039/c7cc06196j
rsc.li/chemcomm
A facile and efficient approach for the synthesis of spirooxindoles has Recently, remote C–H activation via intramolecular Heck reaction
been developed via the coupling of spirocyclic C,C-palladacycles with attracted considerable interests.8 This type of reactions use aryl
CH2Br2. The key spirocyclic palladacycles are generated catalytically halides bearing a tethered alkene as the substrates. The reactions
via remote C–H activation. A range of spirooxindoles can be are initiated by the oxidative addition of aryl halides to Pd(0)
synthesized in good to excellent yields from readily available starting precatalyst, and the subsequent intramolecular migratory inser-
material.
tion forms a s-alkyl Pd(II) intermediate. For some well-designed
structures, the s-alkyl Pd(II) species can activate C–H bonds
Spirooxindole motifs exist in many natural products and bioactive at appropriate sites, forming spirocyclic C,C-palladacycles. In this
molecules.1 Due to their biological properties, spirooxindoles are cascade reaction, C–H bonds distal to the initial halo group are
good targets for drug candidates and clinical pharmaceuticals.2 cleaved. For C–H activation reactions using directing groups, C–H
Consequently, developing innovative methods for the synthesis bonds proximal to the directing groups are usually activated. The
of spirooxindoles and synthesizing novel spirooxindole derivatives remote C–H activation overcomes this limitation, and represents
have been the focus of organic chemists. Although a variety of a new strategy to expand substrate scope of C–H activation
approaches are available,3 continuous efforts should still be reactions. However, the reactivity of this spiropalladacyle remains
devoted to seeking more facile and efficient reactions for the underexplored. Although several intramolecular cyclization
synthesis of this type of significant molecules.
reactions of the palladacycles have been developed (Fig. 1a),9
Our group has been interested in palladacycles, in particular intermolecular reactions are rare. In 2014, the Shi group
those consisting of two carbon–Pd bonds.4 Due to their unique reported that the C,C-palladacyles could be captured with
structures, this type of palladacycles may have novel reactivities,5 diaziridinone (Fig. 1b).10a Subsequently, Garcıa-Lopez and
and the two carbon–Pd bonds offer opportunities to develop new Lautens reported the reaction of the palladacycles with benzynes
´
´
reactions, particularly for the construction of cyclic strucutres. independently (Fig. 1c).10b,c Most recently, the Garcıa-Lopez
Recently, we found that dibenzopalladacyclopentadienes derived group found that carbenoids could also couple with the pallada-
from 2-iodobiphenyls exhibited distinct reactivities, and devel- cycles (Fig. 1d).10d Although this excellent reaction provides a
oped some synthetically useful reactions.6 It should be noted that novel method for the synthesis of spirooxindoles, the products
the dibenzopalladacyclopentadienes were obtained via C–H acti- were limited to those bearing two a-substituents, with one of
vation of 2-iodobiphenyls. The majority of current C–H activations
´
´
rely on the use of directing groups.7 In the formation of the
dibenzopalladacyclopentadienes, the reactions were initiated by
the oxidative addition of aryl iodides to Pd(0) precatalysts, which
represents a complementary strategy for C–H functionalization.
Inspired by the success in dibenzopalladacyclopentadiene chem-
istry, we sought to explore the reactivities of other palladacycles.
School of Chemical Science and Engineering, Shanghai Key Laboratory of Chemical
Assessment and Sustainability, Tongji University, 1239 Siping Road, Shanghai,
200092, P. R. China. E-mail: zhangyanghui@tongji.edu.cn;
Web: http://zhangyhgroup.tongji.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures,
Fig. 1 Remote C–H functionalization through s-alkyl Pd(II) intermediates.
Chem. Commun., 2017, 53, 10429--10432 | 10429
characterization data and copies of spectra. See DOI: 10.1039/c7cc06196j
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Table 1 Conditions surveya
them being ester group. In addition, labile a-diazocarbonyl com-
pounds had to be used. During the preparation of this manuscript,
the Lautens group described the reaction of such spiropalladacycles
with alkynes (Fig. 1e).10e This elegant reaction features excellent
regioselectivity for unsymmetrical alkynes. Furthermore, the
Zhu group proposed that the intermolecular trapping of aza-
palladacycles could be involved in the Pd-catalyzed hetero-
annulation between oximes and benzynes.10f On the other
hand, it has been reported that CH2Br2 can react with pallada-
cycles including dibenzopalladacyclopentadiene to form cyclic
compounds.6c,11 In these reactions, two C–C bonds were formed
and a methylene group was introduced. As a very common
and low-cost chemical, CH2Br2 is a desirable reagent for the
development of organic reactions. We envisioned that the spiro-
cyclic C,C-palladacycle obtained via the remote C–H activation
could also react with CH2Br2, which would provide a new
approach for the synthesis of spirooxoindoles.
We commenced our study by using acrylamide s1 as the
model substrate. Therefore, s1 was treated with 2.0 equivalent
of CH2Br2 under palladium catalysis in DMA. Whereas s1 failed
to react with CH2Br2 in the presence of Na2CO3 or Cs2CO3 as
the base (Table 1, entries 1 and 3), the desired spirooxindole
product p1 was formed by using K2CO3 or KHCO3 (entries 2 and
4). The yield increased to 28% by the addition of 20 mol% of
PPh3 (entry 5). Encouraged by this result, we sought to improve
the yield by screening other phosphine ligands. The yield was
further improved to 36% when P(o-tol)3 was employed (entry 6).
However, the use of other ligands including the bidentate ones
led to lower yields (entries 7–10). Since the catalytic cycle was
expected to start with Pd(0), we envisioned that a reductant
should promote the reaction. Gratefully, although the yield
remained almost unchanged in the presence of isopropyl
alcohol (entry 11), it was dramatically enhanced to 79% when
2.0 equivalent of triethylamine was used (entry 12). The reaction
was much less efficient in other solvents except DMF, which gave
a slightly lower yield (entries 14–18). Notably, the yield was
improved to 83% in the presence of TBAB (entry 19), and further
promoted to 93% by using 0.5 equivalent of TBAI (entry 20).12
After achieving the excellent yield, we turned to further optimize
Entry
Base
L
Red.
Sol.
Yield (%)
1
2
3
4
5
6
7
8
Na2CO3
K2CO3
Cs2CO3
KHCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
—
—
—
—
—
—
—
—
—
—
—
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
NMP
THF
Trace
6
Trace
5
28
36
14
9
23
7
34
79
40
72
55
—
PPh3
P(o-tol)3
P(o-MeOPh)3
PCy3
dppm
dppe
9
—
—
10
11
12
13
14
15
16
17
18
19b
20c
21c,d
22c,e
23c,f
24c,g
25c,h
26c,i
27c,j
28c,k
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
IPA
TEA
DIPEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
MeCN
27
26
Dioxane
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
83
93 (90)l
82
—
87
93
74
93
68
62
a
Reaction conditions: s1 (0.2 mmol), Pd(OAc)2 (10 mol%), L (20 mol%
for monodentate ligand and 10 mol% for bidentate ligand), base
(4.0 equiv.), reductant (2.0 equiv.), CH2Br2 (2.0 equiv.), solvent (2 mL).
The yields were determined by 1H NMR analysis of crude reaction
b
mixture using C2H2Cl4 as the internal standard. TBAB = 0.5 equiv.
c
d
e
f
TBAI = 0.5 equiv. Pd(OAc)2 = 5 mol%. No Pd. CH2Br2 = 1.1 equiv.
g
h
i
j
CH2Br2 = 3.0 equiv. K2CO3 = 3.0 equiv. K2CO3 = 5.0 equiv. TEA =
k
l
1.0 equiv. TBAI = 0.2 equiv. Isolated yield. dppm = bis(diphenyl-
phosphino)methane, dppe = bis(diphenylphosphino)ethane, IPA =
isopropanol, TEA = triethylamine, DIPEA = N,N-diisopropylethylamine,
TBAB = tetrabutylammonium bromide, TBAI = tetrabutylammonium
iodide.
the reaction conditions by investigating the impact of the molar the substrates containing an ortho- or para-methyl group were
equivalents of the reagents on the reaction. First, we reduced the suitable, and the reactions were high-yielding (p2–3). The spiro-
catalyst loading to 5 mol%. Unfortunately, the yield decreased to oxindoles bearing a methoxy or phenyl group could be synthe-
83% (entry 21). The desired product was not observed when sized in good yields (p4–5). The fluoro and chloro groups were
Pd(OAc)2 was removed, which indicates that the reaction is a well-tolerated, and the corresponding spirooxindoles were
Pd-catalyzed process (entry 22). It should be noted that a yield of formed in excellent yields (p6–p8). The acrylamide bearing a
87% was still obtained when 1.1 equivalent of CH2Br2 was used, bromo group was also reactive, albeit in a low yield (p9).
which implies that the domino reaction is very efficient (entry 23).
Next, we investigated the performance of acrylamides bearing
However, the yield failed to be improved even in the presence of different substituents on the benzene rings with the iodo group.
3.0 equivalent of CH2Br2 (entry 24). 4.0 Equivalent of K2CO3 was Methyl groups at the meta- or para-position were compatible,
necessary and sufficient to afford the high yield (entries 25 and 26). furnishing methylated spirooxindoles in high yields (p10–11).
Finally, the yield decreased when the amount of TEA or TBAI was The substrates containing electron-withdrawing groups, such as
reduced (entries 27 and 28).
ester (p12), cyano (p13), and trifluoromethyl (p14), underwent
With the optimized conditions in hand, we then explored the domino reaction smoothly. Notably, fluoro (p15–16), chloro
the substrate scope of the spirooxindole-forming protocol. (p17–18), and even bromo (p19) groups survived under the stan-
First, we examined the compatibility of functionalities on the dard conditions, and the corresponding products were formed in
phenyl groups linked to the double bonds. As shown in Scheme 1, yields ranging from 73% to 93%.
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Scheme 3 Mechanistic studies.
due to steric encumbrance (p28). The trifluoromethyl group
almost had no impact on the reaction (p29), and substrate s30,
containing two fluoro groups also reacted with CH2Br2 in
a good yield. 2-Methylallyl and cyanomethyl groups on the
nitrogen atoms of acrylamides s31 and s32 were tolerated,
affording product p31 and p32 in moderate yields. It should
be mentioned that one of the intramolecular cyclization reactions
of spiropalladacycles also formed spirooxindoles as the final
products.9d
Scheme 1 Substrate scope for the reactions starting from aryl iodides.
To investigate if the reactions proceeded via palladacycles as
the intermediate, we prepared complex c1 starting from s1 and
Pd(PPh3)4 (Scheme 3).10c When palladacycle c1 that contains
two PPh3 ligands was subjected to the standard conditions,
spirooxindoles p1 was formed, albeit in a low yield. The low
yield could result from the negative effect of the PPh3 on the
reaction. To prove this assumption, the reaction of s1 and
CH2Br2 was carried out using Pd(PPh3)4 as the catalyst, and it
was found that the yield decreased dramatically to 37%. These
experimental results indicate that PPh3 could suppress the
formation of the spirooxindole product, and also provide evidences
to support that the palladacycle acted as the key intermediate in
the reaction.
Moreover, the reactivity of substrates containing different
N-substituents was investigated. The reactions of the acrylamides
bearing an ethyl or n-butyl group on the nitrogen atoms were
high-yielding (p20–21). 2-Ethoxy-2-oxoethyl and benzyl groups
were tolerated, and the spirooxindole products were formed in
99% yields (p22–23). The acrylamides containing no substituents
on the nitrogen atom and the ester analogue were unreactive
under the reaction conditions (p24–25). However, the substrate
containing an ether linkage was suitable, although the yield was
low (p26).
Aryl bromides were also reactive enough to undergo the
cascade reaction. As shown in Scheme 2, the bromo analogue
s27 had similar reactivity to s1, furnishing the spirooxindole
product p1 in 91% yield. The substrate scope with the respect of
bromides was also explored. The presence of a methyl group
ortho- to the bromide resulted in a much lower yield, probably
On the basis of the above experimental results and the
previous reports,10,11b a tentative mechanism was proposed as
shown in Scheme 4. The catalytic cycle starts with the oxidative
addition of the halide to Pd(0) to form Pd(II) species A, which is
Scheme 2 Substrate scope for the reactions starting from aryl bromides.
Scheme 4 Proposed mechanism.
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There are no conflicts to declare.
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