Cobalt/Bisoxazolinephosphine-Catalyzed Asymmetric Alkynylation of Isatins

Article abstract of DOI:10.1021/acs.orglett.0c01486

A new catalyst system based on Co(OAc)2/bisoxazolinephosphine has been developed to catalyze the direct addition of terminal alkynes to isatins under base-free conditions. Chiral propargyl alcohols with an oxindole skeleton could be prepared in up to 99% yield and 99% ee with the help of the chiral tridentate ligand. A variety of functionalized aliphatic or aromatic alkynes and isatins were utilized in this method, and gram-scale synthesis could be achieved with 1 mol % catalyst.

Full text of DOI:10.1021/acs.orglett.0c01486

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Letter
Cobalt/Bisoxazolinephosphine-Catalyzed Asymmetric Alkynylation
of Isatins
Jia-Feng Chen and Changkun Li*
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ABSTRACT: A new catalyst system based on Co(OAc)2/
bisoxazolinephosphine has been developed to catalyze the direct
addition of terminal alkynes to isatins under base-free conditions.
Chiral propargyl alcohols with an oxindole skeleton could be
prepared in up to 99% yield and 99% ee with the help of the chiral
tridentate ligand. A variety of functionalized aliphatic or aromatic
alkynes and isatins were utilized in this method, and gram-scale
synthesis could be achieved with 1 mol % catalyst.
Scheme 1. Asymmetric Catalysis by Cobalt and Chiral
Bisoxazolinephosphine Ligands
he transition-metal-catalyzed direct addition of terminal
alkynes to unsaturated carbon−carbon or carbon−
T
heteroatom bonds provides not only atom-economic methods
to prepare complex molecules with versatile alkyne functions
but also an opportunity to construct chiral scaffolds.1 Although
a variety of metals, for example, Zn,2 Cu,3 Rh,4 Ir,5 Co,6 Ni,7 or
Ag,8 have been reported to catalyze the asymmetric
functionalization of terminal alkynes with the help of chiral
ligands, there is still much room to develop new catalyst
systems to solve the problems such as the low reaction
efficiency, homocoupling of terminal alkynes, or the use of
precious transition metal catalysts and a large amount of
alkynes. Recently, we reported the Co(OAc)2/triphos-
catalyzed gem-cross-dimerization of the aromatic alkynes and
aliphatic alkynes, in which an internal acetate was proposed to
promote the formation of Co(II)-acetylide intermediate
(Scheme 1, A).9a We envisioned that not only is the Co(II)-
acetylide intermediate able to coordinate with another alkyne,
but also it is possible to activate carbonyl groups to accelerate
the addition to carbon−heteroatom double bonds. The
simultaneous activation of the terminal alkyne and carbonyl
group within one catalyst was expected to improve the catalysis
efficiency. On the other hand, chiral tridentate bisoxazoline-
phosphine (NPN*) ligand was successfully used in the Co-
catalyzed regio- and enantioselective allylic amination and
alkylation reactions (Scheme 1, B).10 NPN* ligands were
proven to be suitable ligands to provide a chiral environment
in the cobalt complexes. Inspired by the two reactions above,
we expect that Co(OAc)2/NPN* can be a new highly reactive
catalyst in the enantioselective direct addition of terminal
alkynes to carbonyl groups.
Received: April 29, 2020
The 3-substituted 3-hydroxyoxindole structure can be found
in many natural products and biologically active molecules.11
The highly enantioselective addition of alkynes to isatin
derivatives has been realized only recently. Liu12 and Guo13
reported the elegant Cu(I)-catalyzed addition reactions in the
https://dx.doi.org/10.1021/acs.orglett.0c01486
© XXXX American Chemical Society
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A

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presence of base with chiral guanidine and phosphine ligands,
respectively, in which a 3 day reaction time is normally
necessary. The Zn/chiral hydroxyl-oxazoline-catalyzed version
was reported by Chen. However, 20 mol % Zn complex and 3
equiv of alkynes have to be used.14 Maruoka developed the
hybrid catalyst system with noble metal AgOAc and chiral-
phase-transfer-catalyst to promote the addition to trityl
protected isatins in high yields and selectivities.15 Herein, we
substituted R1 were tested (entries 6 and 7). The reaction with
L8 derived from the 2-amino-1,2-diphenylethanol gave lower
yield and enantioselectivity (entry 8). Chiral pyridine
bisoxazoline ligands (pybox) lead to no conversion (see the
Supporting Information). The control experiment without
ligand affords no product (entry 9). The reaction with
Co(OBz)2 as the catalyst precursor leads to comparable yield
and ee (entry 10). Some other salts from the first row
transition metals were examined in the presence of L5. The
acetate salts of Fe, Cu, and Zn are not able to catalyze the same
reaction (entries 11, 13, and 14). Reaction by Ni(OAc)2 gave
3aa with the same level 98% ee, although a lower 67% yield
was obtained (entry 12). The absolute configuration of 3aa
was assigned to be S by single-crystal X-ray diffraction analysis.
With the optimized reaction conditions in hand, we first
examined the scope of the isatins (Table 2). The effect of
present our preliminary result on the Co(OAc)2/NPN*Ph,Ph
-
catalyzed asymmetric alkynylation of isatins (Scheme 1, C).
Chiral propargyl alcohols with the oxindole skeleton could be
prepared in up to 99% yield and mostly 99% ee from alkyl, aryl
or silyl alkynes and unprotected isatins under base-free
conditions. Different useful function groups could be tolerated
under this condition, and gram-scale synthesis was achieved
with 1 mol % Co-complex.
We began our studies with the unprotected isatin 1a and
phenylacetylene 2a as the model substrates (Table 1). Several
a
Table 2. Reaction Scope of Isatins
Table 1. Optimization of Co-Catalyzed Asymmetric
a
Alkynylation of Isatin
b
c
entry
R, R′
3
yield (%)
ee (%)
1
2
3
4
5
6
7
8
5-MeO, H
5-CF3O, H
5-F, H
5-Cl, H
5-Br, H
5-NO2, H
7-CF3, H
7-CO2Me, H
4,7-Cl2, H
H, Me
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
97
95
96
99
96
97
92
98
78
86
91
92
83
99
99
99
99
99
98
99
99
92
98
95
97
98
9
b
c
entry
catalyst precursor
ligand
yield (%)
ee (%)
10
11
12
13
1
2
3
4
5
6
7
8
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OBz)2
L1
L2
L3
L4
L5
L6
L7
L8
99
<5
99
92
96
99
93
76
<5
92
<5
67
<5
<5
29
H, Ph
H, Bn
H, allyl
12
0
99
97
97
83
a
All reactions were run with 5 mol % cobalt catalyst and 5 mol %
b
ligand on a 0.25 mmol scale at 30 °C for 20 h. Yield of isolated
product. The enantiomeric excess values were determined by HPLC
c
analysis with a chiral column.
9
different electron-donating or electron-withdrawing groups at
the 5-position in the unprotected isatin was evaluated (entries
1−6). Functional groups including methoxide, halogens, and
the nitro group could be tolerated. 95−99% yields and 98−
99% ee’s were obtained for 3ba−3ga. CF3 and CO2Me
substituents at the 7-position have a neglectable influence on
the reaction efficiency and selectivities (entries 7 and 8).
Slightly reduced yield and ee were obtained when the 4,7-
dichloroisatin was used (entry 9). The substituent effect on the
nitrogen atom in isatins was further tested. Simple methyl,
phenyl, benzyl, and allyl groups substituted isatins could be
converted to the propargyl alcohols smoothly in excellent
enantioselectivities, albeit with slightly reduced yields (entries
10−13).
The scope of the aromatic alkynes was studied with the
unprotected isatin 1a as the model substrate (Table 3). First,
the reaction with 1.2 equiv of simple phenylacetylene 2a could
be conducted at a 10 mmol scale under the catalysis of 1 mol %
cobalt complex (entry 1). 2.44 g of 3aa was isolated in 99%
yield and 98% ee, which indicates that the reaction could be
used in the gram-scale synthesis. Bromides at para-, meta-, and
10
11
12
13
14
L5
L5
L5
L5
L5
99
98
Fe(OAc)2
Ni(OAc)2
Cu(OAc)2
Zn(OAc)2
a
All reactions were run with 5 mol % catalyst precursor and 5 mol %
ligand on a 0.25 mmol scale at 30 °C for 20 h; the ellipsoids of 3aa
b
were drawn at the 30% probability level. Yield of isolated product.
c
The enantiomeric excess values were determined by HPLC analysis
with a chiral column.
bisoxazolinephosphine ligands with different R2 substitutions
on the oxazoline moiety were evaluated first in ethanol at 30
°C. To our delight, the high efficiency was observed with
isopropyl-, cyclohexyl-, benzyl-, and phenyl-based ligands (L1,
L3−L5). Among them, reaction with L5 leads to the isolation
of 3aa in 96% yield and 99% ee (entry 5). However, less than 5
mol % of 3aa was obtained with L2 bearing a bulky t-butyl
group (entry 2). A neglectable effect was observed when
ligands with an electron-donating or withdrawing phenyl
B
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a
a
Table 3. Reaction Scope of Aromatic or Alkenyl Alkynes
Table 4. Reaction Scope of Aliphatic Alkynes
a
All reactions were run with 5 mol % cobalt catalyst and 5 mol %
ligand on a 0.25 mmol scale at 30 °C for 20 h unless otherwise noted.
b
c
Yield of isolated product. The enantiomeric excess values were
a
All reactions were run with 5 mol % cobalt catalyst and 5 mol %
d
determined by HPLC analysis with a chiral column. The reaction
ligand on a 0.25 mmol scale at 30 °C for 20 h unless otherwise noted.
was conducted at the 10 mmol scale with 1 mol % Co(OAc)2 and L5
at 40 °C for 30 h. At 0 °C.
b
c
Yield of isolated product. The enantiomeric excess values were
e
d
determined by HPLC analysis with a chiral column. The reaction
was conducted at the 10 mmol scale with 1 mol % Co(OAc)2 and L5 f
e
at 60 °C for 30 h. At 60 °C.
ortho-positions could be tolerated in this reaction condition
without erosion of efficiency and selectivities (entries 2−4).
The function groups like electron-withdrawing aldehyde,
cyano, trifluoromethyl, and ester groups have neglectable
influence on the yields and ee’s (entries 5−8), while the
reaction of 1i with a strong electron-withdrawing nitro group
leads to a 69% yield (entry 9). Terminal aromatic alkynes with
electron-donating groups could be converted to the products 3
with high yields and ee’s, in which the protection of the free
amino and hydroxyl groups is not necessary (entries 10−12).
Alkynes with heterocyclic 3-thiophenyl and 3-pyridyl groups or
alkenyl substitutions were also utilized in this direct addition
reaction to give the corresponding propargyl alcohols in
excellent yields and enantioselectivities (entries 13−16).
The reaction of aliphatic alkynes is normally more sluggish
compared to aromatic alkynes, which is probably due to the
lower acidity of aliphatic alkynes.12,13 In the Co(OAc)2/L5
system, this problem could be easily solved by raising the
reaction temperature from 30 to 40 °C. As shown in Table 4,
the reactions of simple n-octyl, benzyl, and cyclopropyl
substituted alkynes with 1a afforded products 5aa−5ac in
high yields with excellent enantioselectivities (entries 1−3).
Terminal alkynes with primary and even tertiary hydroxyl
groups could react under the same condition without
protection to give the diols in high efficiency and selectivities
(entries 4−7). Similarly, the reaction of 1a and 1.2 equiv of 4e
could be conducted with 1 mol % Co(OAc)2 and L5 in a 10
mmol scale (entry 5). 1.84 g of 5ae was isolated in 85% yield
and 98% ee. Other functional groups like halogens, ether,
tosylate, sulfide, amide, cyano, and phthalimide in aliphatic
alkynes could be tolerated without significant influence on the
outcome of the reactions. 5ah−5ao were isolated in 81−98%
yields and 99% ee’s (entries 8−15). Finally, trimethylsilyl
acetylene 4p was successfully applied in this addition reaction
to afford 5ap, which allows the synthesis of the terminal
propargyl alcohol by removing the TMS group (entry 16).
The structure of the cobalt complex was investigated to
understand the role of the chiral ligand. As shown in Scheme 2,
L5-Co(OBz)2·H2O was synthesized in 80% yield by mixing
Co(OBz)2 and L5 in dioxane. A crystal suitable for single-
Scheme 2. Structure of the Chiral Cobalt Complex with
Ellipsoids at the 15% Probability Level
C
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crystal X-ray diffraction analysis was obtained by slow diffusion
of cyclohexane to the dioxane solution. In the solid state,
Co(II) adopts a six-coordinate octahedron geometry with one
extra water molecule. The benzoate anions coordinate with
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01486.
■
sı
1
cobalt in a k mode. Similar to the Co(II)/NPN* and Co(I)/
NPN* complexes we isolated previously,10a the NPN
tridentate ligand occupies half of the coordination sphere in
the facial manner and provides the chiral environment for the
addition step.
Detailed experimental procedures, characterization data,
1
copies of H and 13C NMR spectra, and X-ray crystal
structure of 3aa and Co(OBz)2·L5 (PDF)
Accession Codes
Based on the literature reports and the experiments above, a
catalytic cycle was proposed in Scheme 3. The exchange of
CCDC 1989113 and 1989116 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 3. Proposed Catalytic Cycle
AUTHOR INFORMATION
Corresponding Author
■
Changkun Li − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and Chemical
Engineering, Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240,
China; orcid.org/0000-0002-4277-830X; Email: chkli@
sjtu.edu.cn
Author
Jia-Feng Chen − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and Chemical
Engineering, Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01486
water with terminal alkynes allows the coordination of alkynes
with the cobalt center and enhancement of the acidity of the sp
C−H bond. The internal acetate promoted deprotonation of
the alkynes generates the Co(II)-acetylide intermediate A and
releases HOAc. A undergoes a dissociation of the acetate anion
and the further coordination with the carbonyl groups in
isatins 1 to form cationic intermediate B. The π−π stacking
between the phenyl ring on one of the oxazolines and the
aromatic ring in the isatin molecule locks the orientation of the
other three coordination atoms in only one possibility as
shown in B. Intramolecular addition of the acetylide to the
activated carbonyl group from the Re face of the isatin affords
the Co-alkoxide C with an S chiral center. Ligand exchange of
C with HOAc or solvent EtOH releases the product 3 and
regenerates the active catalyst L5-Co(OAc)2. The oxidative
state of the cobalt complex does not change during the
catalytic cycle.
In summary, we have developed a new catalyst system for
the asymmetric alkynylation of carbonyl groups based on
Co(OAc)2 and chiral bisoxazolinephosphine ligand. The highly
enantioselective direct addition of aryl, alkyl, and silyl terminal
alkynes bearing different functional groups to a variety of isatin
derivatives was realized under neutral conditions. Propargyl
alcohols with the biologically important oxindole skeleton
could be prepared under base-free conditions with 1 mol %
cobalt complex in gram scale. The extension of the scope to
other unsaturated carbon−carbon or carbon−heteroatom
bonds is ongoing in our group.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the National Natural Science
Foundation of China (NSFC) (Grant 21602130) and
Shanghai Jiao Tong University. We thank Prof. Mouhai Shu
from Shanghai Jiao Tong University for the X-ray diffraction
analysis.
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E
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