Enantioselective Alkynylation of Isatins: A Combination of Metal Catalysis and Organocatalysis

Article abstract of DOI:10.1002/chem.202003118

An efficient and catalytic asymmetric alkynylation of isatins has been developed using a bifunctional amidophosphine-urea/AgBF₄ complex as the catalyst. By a combination of metal catalysis and organocatalysis, excellent enantioselectivities (up to 99 % ee) and good yields are achieved. A wide range of both terminal alkynes and isatins are tolerated by this new catalyst system, providing access to structurally diverse propargylic alcohols with tetrasubstituted stereogenic centers in high efficiency.

Full text of DOI:10.1002/chem.202003118

Accepted Article
Accepted Article
Title: Enantioselective alkynylation of isatins: A combination of metal
catalysis and organocatalysis
Authors: Dan Jiang, Pei Tang, Qiuyuan Tan, Zhao Yang, Ling He, and
Min Zhang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202003118
Link to VoR: https://doi.org/10.1002/chem.202003118
01/2020

10.1002/chem.202003118
Chemistry - A European Journal
COMMUNICATION
Enantioselective alkynylation of isatins: A combination of metal
catalysis and organocatalysis
Dan Jiang,†[a] Pei Tang,†[a] Qiuyuan Tan,[a] Zhao Yang,[a] Ling He,*[a] and Min Zhang*[a, b]
[a]
D. Jiang, Dr. P. Tang, Dr. Q. Tan, Z. Yang, Dr. L. He, Prof. M. Zhang
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing
401331, China.
E-mail: heling2015@cqu.edu.cn; minzhang@cqu.edu.cn
[b]
Prof. M. Zhang
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming
650201, China.
[†]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract: We have developed efficient and catalytic asymmetric
alkynylation of isatins using bifunctional amidophosphine–
a
urea/AgBF4 complex as the catalyst. By a combination of metal
catalysis and organocatalysis, excellent enantioselectivities (up to
99% ee) and good yields are achieved. A wide range of both
terminal alkynes and isatins are tolerated by this new catalyst
system, providing access to structurally diverse propargylic alcohols
with tetrasubstituted stereogenic centers in high efficiency.
Bifunctional catalysis by a combination of metal catalysis and
organocatalysis, which integrates the unique activation modes of
organocatalysis with the well-established chemistry of metal
catalysis, has emerged as a promising strategy for developing
new reactions, enabling reactions inaccessible by monocatalysis
systems, and improving the efficiency and stereoselectivity of
existing transformations.[1] Recently, our group developed a new
type of bifunctional amidophosphine–urea ligand that is
equipped with a hydrogen-bond donor and a metal coordination
site on
a
chiral diamine scaffold (Scheme 1a).[2] After
complexation with copper salts, this chiral ligand shows
remarkable catalytic activity and enantioinduction in asymmetric
1,3-dipolar cycloaddition of methacrylonitrile, which is a long-
standing difficult substrate for asymmetric catalysis. The copper-
complexed bifunctional ligand has also been successfully
applied to the enantioselective Mannich reaction of glycine
iminoesters with chemically inert N-phosphinoyl imines.[3] Herein,
to further explore the combination of our ligand with different
metals and address the issues of the low reactivity and
enantioselectivity for catalytic alkynylation of ketones, we report
a new bifunctional amidophosphine–urea/AgBF4 complex that is
efficient for enantioselective alkynylation of isatins (Scheme 1c).
Asymmetric alkynylation of carbonyl compounds with metalated
terminal alkynes, which are generated in situ using
substoichiometric amounts of catalyst and base, is unarguably
the most straightforward and atom-economic approach to
prepare enantioenriched propargylic alcohols.[4] However,
compared with asymmetric alkynylation of aldehydes,[4d,5]
efficient catalytic systems for alkynylation of ketones[6] to
generate propargylic alcohols with tetrasubstituted stereogenic
centers remain underdeveloped, largely because of the low
reactivity of metalated terminal alkynes toward ketones. For
enantioselective alkynylation of isatins,[7–9] efficient catalytic
systems, such as CuI/chiral guanidine, CuI/chiral phosphine
ligand, AgOAc/chiral phase-transfer catalyst,
Scheme 1. Enantioselective alkynylation of isatins.
CuOTf/bisoxazolidine, and Co(OAc)2/bisoxazolinephosphine
have been developed by the groups of Liu,[7a] Guo,[7b]
Maruoka,[7d] Wolf,[7e] and Li,[7f] respectively. 3-Alkynyl-3-hydroxy-
2-oxindoles generated by alkynylation of isatins have been
found to exhibit important biological activities (Scheme 1b). For
example, racemic 3-(hexyn-1-yl)-3-hydroxy-1-methylindolin-2-
one (I) shows excellent biological activity on Echinococcus
multilocularis metacestodes that can cause serious liver damage
in both humans and animals,[9a] and racemic 3-
(cyclopropylethynyl)-3-hydroxy-1,5-dimethylindolin-2-one (II) has
been reported to be more active than efavirenz against HIV-1
replication without significant cytotoxicity.[9b] In addition, because
3-substituted oxindole scaffolds are widely distributed in a vast
range of biologically significant natural products and drug
candidates,[10] 3-alkynyl-3-hydroxy-2-oxindoles have been used
as versatile synthons in a wide variety of synthetic applications
to prepare biologically active spirooxindoles and heterocyclic
compounds.[11] Therefore, development of a new, mild, and
efficient catalytic system for alkynylation of isatins with broad
scope for both alkynes and isatins is highly desirable.
1
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We commenced the study by screening a range of chiral
amidophosphine–urea ligands synthesized by our group for
alkynylation of N-Bn-substituted isatin 1a with phenylacetylene
using AgClO4 (10 mol%) as the metal and DIPEA (20 mol %) as
the base. Initially, in the presence of (1R, 2R)-cyclohexane-1,2-
diamine-derived L1 (12 mol%) as the ligand, the reaction
completed within 24 h to give the desired product 3aa in almost
quantitative yield with moderate enantioselectivity (67% ee)
(Table 1, entry 1). Changing the urea fragment to thiourea
completely blocked the reaction (entry 2, L2), and L3 containing
a squaramide moiety afforded the product in lower yield with
disappointing enantiomeric excess (entry 3). These results
demonstrated that the urea motif is essential for the reactivity
and enantioselectivity. To our delight, a significant increase in
the enantioselectivity was observed using L4 with (1R, 2R)-1,2-
diphenylethylenediamine as the chiral scaffold, giving 3aa in
98% yield with 81% ee (entry 4). Slight structural modification of
the phosphine unit resulted in further improvement of the
enantioselectivity (entry 5, L5). Considering the difficulty in
removing the N-benzyl group of the amide, N-PMB isatin 1b was
synthesized and investigated. The enantioselectivity for 1b was
higher than 1a (entries 4/5 vs entries 6/7). To further improve the
Table 1. Optimization of the reaction conditions.[a]
reaction efficiency,
a range of silver salts with different
counteranions were next examined (entries 8‒13),[12] leading to
the discovery that AgBF4 was the most effective silver salt (entry
13). Additional improvement in the enantioselectivity and
reactivity was achieved when Et3N was used as the base,
providing 3ba in 99% yield with 96% ee in a much reduced
reaction time frame (entry 14). Gram-scale reaction of 1b and 2a
under the optimal reaction conditions provided the product in 98%
yield with 95% ee, which indicated the effectiveness and
practicality of this catalytic system.[12] As expected, the reactions
with the bimethylated ligand L6 and amidourea L7 were not
effective at all (entries 15 and 16), suggesting the crucial roles of
both the amidophosphine and urea moieties in the high reactivity
and effective enantioinduction of the reaction. Additionally, no
reaction took place using L5 or AgBF4 alone, and the
enantioselectivity was reduced when the reaction was
conducted at other temperatures or without MS.[12]
Having established the optimal reaction conditions, we then
investigated the generality of this catalyst system with respect to
terminal alkynes (Table 2). Pleasingly, alkynes with both
electron-donating and electron-withdrawing groups at the para
position of the phenyl group produced the alkynylation products
in good yields with excellent optical purities (3ba–3bg, 90‒96%
ee). The substitution pattern of the phenyl ring had no obvious
effect on the enantioselectivity, and fluoro groups at the ortho,
meta, and para positions of the phenyl group were all tolerated
(e.g., 3bb, 3bh, and 3bk). A heteroaryl-substituted alkyne with a
coordination nitrogen atom also worked well, giving product 3bl
in 98% yield with 90% ee. This catalytic system was also
applicable to alkyl-substituted alkynes, including branched and
cyclic alkyl alkynes, furnishing the corresponding adducts 3bm–
3bp with satisfactory results. Using an alkenyl-substituted alkyne,
the product 3bq was generated with 93% ee, albeit in moderate
yield. The reactions also occurred with various alkynes bearing
other functional groups, such as trimethylsilyl (TMS) and amino
groups, giving access to more functionalized tertiary propargylic
alcohols in high yields with excellent enantioselectivities.
Gratifyingly, the free hydroxyl group was found to be compatible
with the reaction conditions, giving diol compound 3bt in 91%
yield with 90% ee.
Entry
1
substrate
1a
L
[Ag]
t [h]
24
72
57
13
120
43
120
36
48
96
43
96
72
36
96
24
yield[b] [%]
ee[c] [%]
67
–
L1
L2
L3
L4
L5
L4
L5
L5
L5
L5
L5
L5
L5
L5
L6
L7
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgOAc
AgNO3
AgPF6
Ag2CO3
AgOTf
AgBF4
AgBF4
AgBF4
AgBF4
97
0
2
1a
3
1a
51
98
96
98
86
95
98
95
98
98
97
99
0
7
4
1a
81
86
90
93
93
93
92
92
92
95
96
–
5
1a
6
1b
7
1b
8
1b
9
1b
10
11
12
13
14[d]
15[d]
16[d]
1b
1b
1b
1b
1b
1b
The scope of isatins was next investigated using 4-
methoxyphenylacetylene 2f as the pro-nucleophile (Table 3).
Isatins bearing a halide substituent at the 7-position showed
excellent results, delivering products 3cf–3ef in 96–98% yields
with 91–92% ee. The steric hindrance of halide substituents at
1b
0
–
[a] Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), [Ag] (10 mol %), L (12
mol %), DIPEA (20 mol %), 4 Å MS (100 mg), toluene (1.0 mL), 30 °C. [b]
Isolated yield. [c] Determined by chiral HPLC analysis. [d] Et3N (20 mol %)
was used as the base.
the 6- and 5-positions exerted
a slight effect on the
enantioselectivity. The less sterically demanding groups F and
2
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Table 2. Substrate scope of terminal alkynes.[a–c]
Table 3. Substrate scope of isatin derivatives.[a–c]
[a] Reaction conditions: 1 (0.1 mmol), 2f (0.2 mmol), AgBF4 (10 mol %), L5 (12
mol %), Et3N (20 mol %), 4 Å MS (100 mg), toluene (1.0 mL), 30 °C. [b]
Isolated yield. [c] The ee values were determined by chiral HPLC analysis.
[a] Reaction conditions: 1b (0.1 mmol), 2 (0.2 mmol), AgBF4 (10 mol %), L5
(12 mol %), Et3N (20 mol %), 4 Å MS (100 mg), toluene (1.0 mL), 30 °C. [b]
Isolated yield. [c] The ee values were determined by chiral HPLC analysis.
Cl (3ff, 3if, and 3jf) gave higher ee values than the more
sterically demanding groups Br and I (3gf, 3kf, and 3lf). Despite
a significant decrease in the yield to 49%, the reaction was
compatible with the 6-methoxy-substituted isatin substrate,
giving compound 3hf with 88% ee. The reaction with 5-
nitroisatin occurred in high yield with excellent enantioselectivity
(3mf, 99% ee). Isatins with electron-donating groups at the 5-
position, such as 5-OMe (3nf) and 5-OCF3 (3of), were also
competent electrophiles, providing the corresponding propargylic
alcohols with comparable yields and enantioselectivities. The
reaction also smoothly proceeded with 4-halogen-substituted
isatin, giving the corresponding product 3pf in quantitative yield
with 85% ee.
The absolute configuration of 3jf was unambiguously
determined to be R by X-ray crystallography analysis, and the
same absolute configuration was then analogously assigned to
the other products. Based on the experimental results, a
plausible transition state mode is proposed to account for the
high reactivity and enantioselectivity (Figure 1, TS-1 vs TS-2). In
the presence of a base, the phosphine and amide-complexed
silver salt[13] interacts with the terminal alkyne to form a Ag-
Figure 1. Plausible reaction models.
acetylide intermediate.[14] The isatin partner is chemically
activated and spatially orientated by a hydrogen bond between
3
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In summary, we have developed a new catalytic system of
bifunctional amidophosphine–urea ligand-complexed AgBF4 for
catalytic alkynylation of ketones, which has been demonstrated
to be efficient for the asymmetric alkynylation of isatins. By the
combination of metal catalysis and organocatalysis, a wide
range of both alkynes and isatins are well tolerated, providing
access to a series of structurally diverse 3-alkynyl-3-hydroxy-2-
oxindoles with a tetrasubstituted stereogenic center in high
yields with high enantiomeric purities (up to 99% ee).
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21672029, 21702023, 21871033, and
21922102), State Key Laboratory of Phytochemistry and Plant
Resources in West China (P2017-KF08), and Chongqing
Science and Technology Commission (cstc2018jcyjAX0421).
We also thank Mr Xiangnan Gong (CQU) for X-ray
crystallographic analysis.
[7]
Keywords: alkynylation • isatin • metal catalysis • organo-
catalysis • 3-alkynyl-3-hydroxy-2-oxindole
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4
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5
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Entry for the Table of Contents
A highly enantioselective alkynylation of isatins has been developed using a new bifunctional amidophosphine–urea/AgBF4 complex
as the catalyst. By a combination of metal catalysis and organocatalysis, a wide range of both alkynes and isatins are well tolerated
by this catalytic system, providing a series of structurally diverse 3-alkynyl-3-hydroxy-2-oxindoles with a tetrasubstituted stereogenic
center in high yields with high enantiomeric purities (up to 99% ee).
6
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