Pd/Cu-Catalyzed Enantioselective Sequential Heck/Sonogashira Coupling: Asymmetric Synthesis of Oxindoles Containing Trifluoromethylated Quaternary Stereogenic Centers

Article abstract of DOI:10.1002/anie.201913148

An asymmetric palladium and copper co-catalyzed Heck/Sonogashira reaction between o-iodoacrylanilides and terminal alkynes to synthesize chiral oxindoles was developed. In particular, a wide range of CF₃-substituted o-iodoacrylanilides reacted

Full text of DOI:10.1002/anie.201913148

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Accepted Article
Title: Pd/Cu-Catalyzed Enantioselective Sequential Heck-Sonogashira
Coupling: Asymmetric Synthesis of Oxindoles Containing
Trifluoromethylated Quaternary Stereogenic Centers
Authors: Yixin Lu, Xingfeng Bai, Caizhi Wu, and Shaozhong Ge
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10.1002/anie.201913148
Angewandte Chemie International Edition
COMMUNICATION
Pd/Cu-Catalyzed Enantioselective Sequential Heck-Sonogashira
Coupling: Asymmetric Synthesis of Oxindoles Containing
Trifluoromethylated Quaternary Stereogenic Centers
Xingfeng Bai, Caizhi Wu, Shaozhong Ge* and Yixin Lu*
Dedicated to John F. Hartwig for his 55th birthday
Abstract: An asymmetric palladium and copper co-catalyzed
sequential Heck/Sonogashira reaction between o-iodoacrylanilides
and terminal alkynes to synthesize chiral oxindoles was developed.
In particular, a wide range of CF3-substituted o-iodoacrylanilides
reacted with terminal alkynes, affording the corresponding chiral
oxindoles containing trifluoromethylated quaternary stereogenic
centers in high isolated yields with excellent enantioselectivity (94-
98% ee). This asymmetric Heck/Sonogashira reaction provides a
general approach to access oxindole derivatives containing
quaternary stereogenic centers including CF3-substituted ones.
potential -fluorine elimination.[8] There was only one example of
Pd-catalyzed Heck-type cyclization employing CF3-substittued
alkenes, and CF3-groups in starting alkenes were converted to
CF2-groups through -fluorine elimination.[8d] Therefore, it
remains elusive to develop Heck-type asymmetric cyclization
with CF3-substituted alkenes to build CF3-substituted quaternary
stereogenic centers.
During our continuous effort in developing enantioselective
protocols to make chiral oxindoles,[9] we became interested in
the synthesis of chiral oxindoles containing trifluoromethylated
quaternary stereocenters at the C3-position. We envisioned that
the alkylpalladium species (I in Figure 1B) resulting from the
carbopalladation step would contain fluorine atoms at the -
carbon, which suppresses the potential -fluorine elimination
and thus enables the retention of CF3-substituents in final
oxindole products. Herein, we report a highly enantioselective
palladium and copper co-catalyzed sequential Heck
cyclization/Sonogashira reaction[10] of CF3-substituted o-
iodoacrylanilides with alkynes to access chiral 3,3-substituted
oxindoles (Figure 1B).[10g] In addition, we also showed that other
alkyl- or aryl-substituted o-iodocrylanilides underwent this
asymmetric reaction to afford propargyl-substituted oxindoles
with excellent enantioselectivities.
Organofluorine compounds have found broad applications in
medicinal chemistry and agrochemistry because of their stability,
reactivity, and unique biological activities.[1] On the other hand,
chiral 3,3-disubstituted oxindole cores are important structure
motifs that can be frequently found in many bioactive natural
products and synthetic analogues.[2] Therefore, it is highly
desirable to develop enantioselective protocols to access
fluorine-containing 3,3-disubstituted oxindoles because the
incorporation of fluorine into these oxindole molecules may
endow them new biological properties. Indeed, it has been
recently shown that the introduction of a fluorine atom or a
trifluoromethyl group to the C3 position of an oxindole molecule
enhances its biological activities.[3] While enantioselective
approaches to prepare chiral 3-fluorinated oxindoles have been
well established,[4] methods to prepare enantio-enriched
oxindoles containing CF3-substituted quaternary stereogenic
carbons[5] at the C3-position are rather limited. To the best of our
knowledge, asymmetric radical trifluoromethylation of 3-
substituted oxindoles is the only known reaction that affords
enantio-enriched 3-trifluoromethyloxindoles, which has been
recently disclosed by Katayev and co-workers (Figure 1A).[6]
In recent years, enantioselective intramolecular Heck
reactions of anilide-tethered haloarene-alkenes have been
emerging as effective approaches to prepare chiral oxindole
cores.[7] However, only aryl- or alkyl-substituted alkenes have
been studied for these asymmetric reactions, and the substrates
that contain CF3-substituted alkenes have not been employed
for this Heck-type enantioselective cyclization. In general, Heck
reactions of CF3-substituted alkenes have been much less
studied than those of common alkenes, and this is largely due to
A) Asymmetric radical trifluoromethylation of 3-subtituted oxindoles[6]
R2
R2
CF3
MgBr2/chiral PyBOX ligand
Electrophilic CF3 reagents
R1
O
R1
O
N
N
PG
PG
B) Pd/Cu-catalyzed asymmetric Heck/Sonogashira sequential coupling (this work)
I
F3C
O
R2
R1
Pd/Cu/chiral ligands
R2
R1
O
CF3
N
N
a
PG
F C
3g
PG
[Pd(L*)]
b
R1
O
N
PG
carbopalladation species (I)
Figure 1. Enantioseletive synthesis of CF3-substituted oxindoles.
We initiated our study on this sequential asymmetric Heck-
Sonogashira coupling reaction by identifying reliable conditions
and selective palladium catalysts for the reaction between CF3-
substituted o-iodoacrylanilide 1a and phenylacetylene 2a with an
attempt to synthesize chiral 3-trifluoromethylated oxindole 3a.
The results of selected evaluation experiments are summarized
in Table 1. First, we chose a palladium catalyst generated in situ
from [(η3-C3H5)PdCl]2 and a Josiphos derivative L1 to test
various copper cocatalysts, bases, solvents, and temperatures
for this model reaction (see the Supporting Information for the
[*]
Dr. X.-F. Bai, C. Wu, Prof. Dr. S. Ge, Prof. Dr. Y. Lu
Department of Chemistry, National University of Singapore
3 Science Drive 3, 117543, Singapore (Singapore)
E-mail: chmgsh@nus.edu.sg
chmlyx@nus.edu.sg
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201913148
Angewandte Chemie International Edition
COMMUNICATION
details), and found that the reaction conducted in tert-butanol
proceeded to offer full conversion of 1a in 20 h at 80 C in the
presence of CuI as co-catalyst and DABCO/Ag3PO4 as bases.
This reaction yielded the desired oxindole product 3a in 75%
isolated yield, but with modest enantioselectivity (72% ee).
methyl (1a), para-methoxyphenyl (PMB, 1b) and benzyl (1c)
groups, reacted with phenylacetylene 2a and afforded chiral
CF3-substituted oxindoles 3a–3c in high yields with high
enantioselectivities (>95% ee). The absolute configuration of 3c
was assigned as (S) by single crystal X-ray diffraction analysis.
In addition, several other CF3-substituted o-iodoacrylanilides
containing various substituents, such as fluoro (1d), chloro (1e),
bromo (1f), methyl (1g) and methoxy (1h) groups, on the
anilides also reacted with phenylacetylene 1a, yielding chiral
oxindoles 3d–3h with excellent enantioselectivities (9698% ee).
Furthermore, we also showed that a wide range of aryl- and
alkyl-substituted terminal alkynes (2i–2p) reacted with CF3-
substituted o-iodoacrylanilide 1a to produce the corresponding
chiral oxindoles (3i–3p) in good yields (4682%) and excellent
enantioselectivities (9698% ee).
Table 1. Evaluation of chiral ligands for this Pd-catalyzed asymmetric
Heck/Sonogashira reaction of 1a with phenylacetylene 2a.[a]
Table 2. Scope of CF3-substituted o-iodoacrylanilides and alkynes.[a]
[(h3-allyl)PdCl]2 (2 mol%)
F3C
I
CuI (4 mol%)
R3
O
R1
L4 (9 mol%)
+
O
R1
R3
N
DABCO (2.0 equiv)
Ag3PO4 (0.33 equiv)
tBuOH, 80 °C, 20 h
N
2
R2 CF3
R2
3
1
F3C
Ph
F3C
Ph
F
O
O
N
N
R
Bn
R = Me, 3a, 75% yield; 97% ee
R = PMB, 3b, 78% yield; 95% ee
R = Bn, 3c, 88% yield; 95% ee
3d, 52% yield; 97% ee
Structure of 3c
F3C
Ph
F3C
F3C
Ph
Ph
Cl
Br
MeO
[a] Reaction conditions: 1a (0.200 mmol), phenylacetylene 2a (0.300 mmol),
[(η3-C3H5)PdCl]2 (8.0 mol), ligand (18.0 mol), CuI (8.0 mol), DABCO (1,4-
diazabicyclo[2,2,2]octane, 0.400 mmol), Ag3PO4 (0.066 mmol), t-BuOH (1 mL),
80 C, 20 h, yields were determined by NMR analysis with CH2Br2 as internal
standard; ee was determined by chiral HPLC analysis. [b] The other
enantiomer of 3a was obtained. ND: Not Determined.
O
O
N
O
N
N
Bn
Bn
PMB
3e, 58% yield; 96% ee
3f, 40% yield; 98% ee
3g, 82% yield; 97% ee
F3C
F3C
F3C
Ph
Me
O
O
N
O
F
N
F
N
Subsequently, we evaluated a series of chiral ligands for this
reaction under these identified conditions. First, we tested
several other chiral ligands of Josiphos family (L2–L6) for this
reaction. The reaction conducted with a palladium catalyst
containing L2 yielded only a trace amount of cyclic product 3a
(<5%) and the major product for this reaction was the uncyclized
compound 3a’, which was formed by direct Sonogashira
coupling between 1a and 2a. To our delight, the reaction run
with L3-ligated palladium catalyst afforded 3a with high
enantioselectivity (91%), albeit in low yield (35%). In particular,
the reaction employing ligand L4 proceeded to full conversion of
1a, furnishing 3a in 85% yield with excellent enantioselectivity
(97% ee). Catalysts generated from L5 or L6, two Josiphos
derivative ligands with aryl groups on both phosphine atoms,
were less enantioselective for this Pd-catalyzed transformation.
In addition, we also tested other chiral ligands, such as
(R,R,S,S)-duanphos (L7), (S)-binap (L8), (R)-difluorphos (L9),
and (S)-iPr-Phox (L10), but these reactions produced the
desired oxindole 3a either in low yields or with modest
enantioselectivities.
Me
Me
PMB
3h, 91% yield; 95% ee
3i, 72% yield; 96% ee
3j, 81% yield; 96% ee
F3C
F3C
F3C
Me
OMe
S
O
O
O
N
N
N
Me
Me
Me
3k, 82% yield; 98% ee
3l, 78% yield; 98% ee
3m, 75% yield; 97% ee
Cl
F3C
F3C
Si(iPr)3
Br
O
N
O
N
N
N
Me
Me
3o, 53% yield; 98% ee
3n, 55% yield; 96% ee
OMe
F3C
F3C
F3C
Me
O
O
N
O
N
PMB
N
Me
Me
3q, 46% yield; 97% ee
3p, 74% yield; 98% ee
3r, 61% yield; 94% ee
[a] Reaction conditions: CF3-substituted o-iodoacrylalinide (0.200 mmol),
alkyne (0.300 mmol), L4 (18.0 mol), and other conditions are identical to
those listed in Table 1.
As asymmetric Pd/Cu-catalyzed sequential Heck/Sonogashira
coupling between alkyl- or aryl-substituted o-iodoacrylanilides
and terminal alkynes to access oxindoles containing quaternary
stereogenic centers remains unknown, we subsequently
extended our study to non-CF3-substituted o-iodoacrylanilides,
and the results are summarized in Table 3. Under the conditions
With the identified catalysts and reliable conditions in hand,
we studied the scope of CF3-substituted o-iodoacrylanilides and
alkynes for this enantioselective transformation, and the results
are summarized in Table 2. o-Iodoacrylanilides containing
various substituents on the anilide nitrogen atom, such as
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10.1002/anie.201913148
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COMMUNICATION
identified for the reaction of CF3-substituted o-iodoacrylanilides,
substrate 4a, the CH3-congener of o-iodoacrylanilide 1a, reacted
with alkyne 2a to afford oxindole 5a in high isolated yield (95%),
but with only modest enantioselectivity (62% ee). Upon the
evaluation of other Josiphos derivative ligands L1–L6 (see
Supporting Information for the details), we found that in the
presence of L2, the reaction between 4a and 1a gave oxindole
5a not only in high isolated yield (90%) but also with excellent
enantioselectivity (96% ee). When catalyzed by this
ligand/palladium combination, a variety of o-iodoacrylanilides
containing various substituents on the alkene unit and the anilide
nitrogen reacted with alkyne 2a to produce the corresponding
chiral oxindoles in high isolated yields (8095%) with high
enantioselectivities (9297% ee). This reaction showed good
functional group tolerance, and several reactive groups, such as
methoxymethyl (5d), siloxyether (5h), chloro (5j and 5p), bromo
(5k), cyano (5l), and carboxylic ester group (5n), could be
tolerated under standard reaction conditions.
intact (Scheme 1, A). The silyl group of 3o could be also readily
removed using TBAF to generate a terminal alkyne product 7 in
85% yield (Scheme 1, A). In addition, the alkyne functionality of
5a underwent annelation with the phenyl group in the oxindole
core to form a tricyclic compound 8 in 75% yield (Scheme 1, B).
The structure of 8 obtained by single X-ray crystal diffraction
analysis confirmed the absolute configuration of compound 5a.
Similarly, the CF3-substituted oxindole 3a also underwent this
annelation to afford compound 9, albeit with a lower yield
(Scheme 1, B). The alkyne functionality in CF3- and CH3-
substituted oxindoles (3l and 5a) could undergo cis-
semihydrogenation in the presence of Lindlar catalyst to afford
Z-alkenes 10a and 10b, respectively, in high isolated yields with
100% enantiospecificity (Scheme 1, C). Furthermore, ozonolysis
of 10a and 10b gave chiral aldehyde-containing oxindoles 11a
and 11b in high yields, respectively (Scheme 1, C). To highlight
the synthetic utility of this Pd/Cu-catalyzed Heck/Sonogashira
coupling, we showcased an enantioselective synthesis of EGIS-
12,233,[11] a potent and selective antagonist for 5-HT6/7 receptors,
by catalytic hydrogenation of chiral oxindole 5p followed by
removal of the methoxymethyl protecting group (Scheme 1, D).
Table 3. Scope of o-iodoacrylanilides and alkynes.[a]
[(h3-allyl)PdCl]2 (2 mol%)
R4
I
CuI (4 mol%)
Ph
O
R1
L2 (9 mol%)
+
O
R1
Ph
N
DABCO (2.0 equiv)
Ag3PO4 (0.33 equiv)
tBuOH, 80 °C, 20 h
N
A)
2
F3C
F3C
F3C
R2 R4
R3
Ph
H
R2
5
TBAF
CAN (3 equiv)
4
O
O
O
CH3CN/H2O
RT, 18 h
N
N
N
Me
Me
Me
Ph
Ph
Ph
R2
H
Me
O
O
3b, 95% ee
O
3o, 96% ee
R2 = Me; R3 = Si(iPr)3
6, 73% yield; 92% ee
7, 85% yield; 95% ee
N
N
N
R2 = PMB; R3 = Ph
Ph
CH2Ph
Me
OEt
B)
R
5a, 95% yield; 62% ee (L4)
5b, 88% yield; 94% ee
5c, 89% yield; 92% ee
Ph
R
5a, 90% yield; 96% ee (L2)
H3CH2C
Ph
O
Me
Ph
Ph
Ph
O
N
TFA, 80 °C, 2 h
N
O
N
Me
O
N
O
N
Me
R = Me, 5a, 96% ee
R = CF3, 3a, 97% ee
R = Me, 8, 75% yield; 95% ee
R = CF3, 9, 36% yield; 96% ee
OMe
Me
OEt
Structure of compound 8
5d, 91% yield; 95% ee
5e, 80% yield; 95% ee
5f, 82% yield; 97% ee
C)
Ar
O
TBSO
Ph
R
Ph
Lindlar catalyst
H2 balloon
Me
R
Ar
Ph
Ph
R
F
O3
CH2Cl2, -78 °C-RT
O
N
O
N
O
N
O
O
EtOAc, 80 °C, 2 h
O
N
N
N
Me
Me
OMe
5h, 95% yield; 96% ee
Me
OMe
OEt
5g, 91% yield; 94% ee
Me
Me
R = CF3, Ar = p-tol, 3l, 98% ee
R = CH3, Ar = Ph, 5a, 94% ee
5i, 90% yield; 96% ee
10a, R = CF3, Ar = p-tol
95% yield; 98% ee
10b, R = CH3, Ar = Ph
71% yield; 94% ee
11a, R = CF3
Me
83% yield; 98% ee
11b, R = CH3
76% yield; 94% ee
Cl
Ph
Ph
Ph
Cl
Br
NC
O
N
O
O
N
N
Cl
OMe
5j, 83% yield; 93% ee
Me
OMe
OMe
5k, 80% yield; 96% ee
5l, 93% yield; 96% ee
Me
N
Ph
Ph
N
Me
D)
N
O
O
N
N
H3CH2C
H3CH2C
N
1, Pd/C (10 mol%)
H2 balloon
THF, RT, 1 h
MeO2C
N
N
Cl
Cl
Cl
OMe
OMe
O
O
5m, 88% yield; 94% ee
5n, 84% yield; 97% ee
N
N
Me
CH3
O
2, TfOH (10 mol%)
TFA, RT, 1 h
Ph
Cl
OMe
Cl
Cl
H
MeO
O
5p, 97% ee
EGIS-12,233, 62% yield; 97% ee
N
N
Me
5o, 83% yield; 94% ee
OMe
Cl
5p, 93% yield; 97% ee
Scheme 1. Further transformations of chiral oxindole products.
[a] Reaction conditions: o-iodoacrylalinide (0.200 mmol), alkyne (0.300 mmol),
L2 (18.0 mol), and other conditions are identical to those listed in Table 1.
In summary, we have developed a highly enantioselective
protocol to synthesize chiral oxindoles containing quaternary
stereogenic centers, particularly trifluoromethylated ones, by
Pd/Cu-catalyzed asymmetric Heck/Sonogashira sequential
coupling reaction. In the presence of chiral palladium catalysts
containing Joshiphos derivative ligands L2 or L4, a wide range
of o-iodoacrylanilides reacted with terminal alkynes to afford the
The chiral oxindole products of these enantioselective Pd/Cu-
catalyzed Heck/Sonogashira coupling reactions can undergo
several enantiospecific organic transformations (Scheme 1). For
example, the p-methoxyphenyl (PMB) group in oxindole 3b
could be removed with CAN reagent to provide unprotected
oxindole 6 in 73% yield while keeping the alkyne functionality
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10.1002/anie.201913148
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COMMUNICATION
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Acknowledgements
S.G. acknowledges the financial support from the Ministry of
Education of Singapore (R-143-000-A93-112). Y.L. thanks the
Singapore National Research Foundation, Prime Minister’s Office for
the NRF Investigatorship Award (R-143-000-A15-281).
Keywords: trifluoromethylated quaternary stereocenters • Heck
reaction • Sonogashira reaction • oxindole • asymmetric catalysis
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This article is protected by copyright. All rights reserved.

10.1002/anie.201913148
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Xingfeng Bai, Caizhi Wu, Shaozhong
Ge* and Yixin Lu*
Page No. – Page No.
Pd/Cu-Catalyzed Enantioselective
Sequential Heck-Sonogashira
Coupling: Asymmetric Synthesis of
Oxindoles Containing
Trifluoromethylated Quaternary
Stereogenic Centers
Trifluoromethylated Oxindoles: A highly enantioselective Pd/Cu-catalyzed
Heck/Sonogashira sequential coupling reaction was developed to prepare chiral
oxindoles containing quaternary stereogenic centers, particularly trifluoromethyated
ones. The synthetic utilities of this enantioselective protocol were exemplified
through several stereospecific derivatizations and the synthesis of EGIS-12,233.
This article is protected by copyright. All rights reserved.