Lanthanide Silylamide-Catalyzed Synthesis of Pyrano[2,3- b]indol-2-ones

Article abstract of DOI:10.1021/acs.orglett.1c01506

A lanthanide silylamide-catalyzed tandem reaction of isatins, diethyl phosphite, and 2,3-diarylcyclopropenones has been developed. A series of pyrano[2,3-b]indol-2-ones were synthesized in high yields. The cooperation of the Lewis acidity of the lanthanide center and the Bronsted basicity of the N(SiMe3)2 anion may be the key factor affecting the catalytic activity of lanthanide amides.

Full text of DOI:10.1021/acs.orglett.1c01506

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Lanthanide Silylamide-Catalyzed Synthesis of Pyrano[2,3‑b]indol-2-
ones
Qifa Chen, Yue Teng, and Fan Xu*
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ABSTRACT: A lanthanide silylamide-catalyzed tandem reaction
of isatins, diethyl phosphite, and 2,3-diarylcyclopropenones has
been developed. A series of pyrano[2,3-b]indol-2-ones were
synthesized in high yields. The cooperation of the Lewis acidity
of the lanthanide center and the Bronsted basicity of the
N(SiMe3)2 anion may be the key factor affecting the catalytic
activity of lanthanide amides.
Scheme 1. Currently Reported Synthetic Routes to
Pyrano[2,3-b]indol-2-ones
used heterocycles occupy a very important position in
bioorganic and medicinal chemistry because of their
F
numerous biological activities and extensive application as
pharmaceuticals. Pyrano[2,3-b]indole, a heterocycle bearing
both pyran and indole moieties, is one of the most important
structural units in pharmaceutical chemistry, and its derivatives
exhibit a range of therapeutic properties, including antimicro-
bial,1 antimalarial,2 antiproliferative,2 and antitumor3 activities.
For example, hyrtimomine A,4 a new alkaloid isolated from the
Okinawan marine sponge Hyrtios sp., shows cytotoxicity
against human epidermoid carcinoma KB cells and murine
leukemia cells, and hyrtimomine B5 is found to be an
anticancer target of phosphoinositide-dependent kinase 1
(PDK1) (Figure 1). Accordingly, these findings have
contributed to an increased demand for the development of
synthetic routes to the pyrano[2,3-b]indole ring system.
Figure 1. Representative biologically active compounds containing
the pyrano[2,3-b]indole scaffold.
As the most important pyrano[2,3-b]indole derivatives,
pyrano[2,3-b]indol-2-ones have garnered considerable research
attention. However, to the best of our knowledge, there are
very few reported methods for the efficient construction of
pyrano[2,3-b]indol-2-one scaffolds. As rare examples, in 1993,
Cacchi6 achieved the first synthesis of pyrano[2,3-b]indol-2-
one using Meldrum’s acid and N-(2-iodophenyl)propiolamide
as substrates through a multistep process (Scheme 1a); in
2006, Grandberg7 reported that the condensation of oxindole
with a 3-fold excess of acetoacetic ester at high temperature
affords pyrano[2,3-b]indol-2-one in 18% yield (Scheme 1b),
and Nagarajan8 developed three metal-free synthetic routes to
pyrano[2,3-b]indol-2-ones (Scheme 1c). More recently,
Received: May 2, 2021
Published: May 28, 2021
https://doi.org/10.1021/acs.orglett.1c01506
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4785−4790
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Zhang9 reported the preparation of a pyrano[2,3-b]indol-2-one
by cesium fluoride-promoted carboxylative cyclization of 3-(1-
phenylethylidene)indolin-2-one via γ-carboxylation using car-
bon dioxide (Scheme 1d). In most of these studies, only one
pyrano[2,3-b]indol-2-one product was prepared and unsat-
isfactory yields were reported. Thus, the development of novel
and highly efficient processes for the synthesis of pyrano[2,3-
b]indol-2-ones is of great value.
a
Table 2. Optimization of Reaction Conditions
temp
time
(h)
yield
(%)
entry
catalyst
(°C)
Lanthanide silylamides are bifunctional compounds that
exhibit both the Lewis acidity of the lanthanide center and the
Bronsted basicity of the silylamino group. They have been
found to be efficient catalysts for a series of valuable
transformations.10 On the other hand, as amphiphilic micro-
cyclic molecules with large ring strain, cyclopropenones have
often been used as building blocks for the construction of
larger molecules.11 Accordingly, in the course of our
development of efficient strategies for building cyclic
compounds,12 we conceived the idea of establishing a method
for the synthesis of pyrano[2,3-b]indol-2-ones using a
lanthanide silylamide as the catalyst and cyclopropenone as
the starting material.
1
2
3
4
5
6
7
[(Me3Si)2N]3La(μ-Cl)Li(THF)3
[(Me3Si)2N]3Nd(μ-Cl)Li(THF)3
[(Me3Si)2N]3Sm(μ-Cl)Li(THF)3
[(Me3Si)2N]3Er(μ-Cl)Li(THF)3
[(Me3Si)2N]3Yb(μ-Cl)Li(THF)3
−
LaCl3
NaN(SiMe3)2
La[N(SiMe3)2]3
LiCl
[(Me3Si)2N]3La(μ-Cl)Li(THF)3
[(Me3Si)2N]3La(μ-Cl)Li(THF)3
[(Me3Si)2N]3La(μ-Cl)Li(THF)3
[(Me3Si)2N]3La(μ-Cl)Li(THF)3
[(Me3Si)2N]3La(μ-Cl)Li(THF)3
[(Me3Si)2N]3La(μ-Cl)Li(THF)3
50
50
50
50
50
50
50
50
50
50
rt
80
110
110
110
110
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1
82
79
73
79
78
0
trace
14
43
0
72
82
90
84
86
87
b
8
9
10
11
12
13
14
15
16
We first investigated the reaction of N-ethyl isatin (1a),
diethyl phosphite (2), and 2,3-diphenylcyclopropenone (3a)
catalyzed by [(Me3Si)2N]3Yb(μ-Cl)Li(THF)3 (Table 1). First,
3
6
a
Reaction conditions: 0.29 mmol of 1a, 0.29 mmol of 2, 0.24 mmol of
a
Table 1. Solvent Screening
3a, 20 mol % catalyst (relative to 3a), 1.0 mL of toluene. Isolated
yields are reported. With 60 mol % NaN(SiMe3)2.
b
1−5), while no reaction was observed in the absence of a
catalyst (entry 6). [(Me3Si)2N]3La(μ-Cl)Li(THF)3 was found
to be slightly more active than the other catalysts.
entry
solvent
THF
DMF
DMSO
MeCN
1,4-dioxane
DME
DCE
PhCl
n-hexane
toluene
yield (%)
Owing to the bifunctionality of lanthanide silylamides,
several comparative experiments were conducted to explore
the origin of their catalytic activity in this reaction. Reactions
with LaCl3 and NaN(SiMe3)2 as the catalyst afforded very little
product, indicating that a Lewis acid or Brønsted base alone
cannot catalyze the reaction (entries 7 and 8).
[(Me3Si)2N]3Ln(μ-Cl)Li(THF)3 may be considered as
chloride-bridged “ate” complexes derived from homoleptic
lanthanide silylamides {Ln[N(SiMe3)2]3}. Accordingly, each
individual component of the catalyst was evaluated (entries 9
and 10). However, the reaction with homoleptic La[N-
(SiMe3)2]3 gave a yield of only 43%, while LiCl was found
to be inactive in this reaction, indicating that the way
La[N(SiMe3)2]3 bonds to LiCl has a remarkable influence
on activity in this system. The reaction temperature and time
were also optimized (entries 11−16). The final yield obtained
from the reaction in toluene under reflux for 1.5 h was 90%.
As a means to optimize catalyst loading, ligands were added
to the reaction system. A series of ligands were investigated
with a 10 mol % loading of [(Me3Si)2N]3La(μ-Cl)Li(THF)3
(Table 3). In the absence of a ligand, the product was obtained
in 50% yield (entry 1). Phenols with bulkier substituents, such
as 4-(tert-butyl)phenol, 2-(tert-butyl)phenol, and 2,6-di(tert-
butyl)-4-methylphenol, did not improve the reactivity
significantly, nor did quinolin-8-ol (L1) (entries 2−7). Salens
(L2 and L3) and N-phenyl-1-(pyrrol-2-yl)methanimines (L4
and L5) also led to unsatisfactory results (entries 8−13). When
β-diketimines derived from pentane-2,4-dione (L6 and L7)
were evaluated (entries 14−17), better results were obtained
and it was found that more sterically hindered ligands lead to
higher reaction yields. Therefore, β-diketimines derived from
1
2
3
4
5
6
7
8
9
10
60
19
43
36
53
54
51
69
57
78
a
Reaction conditions: 0.29 mmol of 1a, 0.29 mmol of 2, 0.24 mmol of
3a, 20 mol % [(Me3Si)2N]3Yb(μ-Cl)Li(THF)3 (relative to 3a), 50
°C, 1.5 h, 1.0 mL of solvent. Isolated yields are reported.
1a and diethyl phosphite were mixed in the presence of 20 mol
% [(Me3Si)2N]3Yb(μ-Cl)Li(THF)3 for 30 min, and then 3a
and THF were added. The mixture was stirred for a further 1.5
h at 50 °C. After workup, the major product was isolated and
identified as the expected product pyrano[2,3-b]indol-2-one.
The yield was 60%. Encouraged by this preliminary result, we
investigated a series of reaction conditions. The results of
solvent screening (Table 1) showed that high-polarity solvents,
such as DMF, DMSO, and MeCN, do not favor the formation
of the product (entries 2−4, respectively), while ethers,
halohydrocarbons, and n-hexane provide only moderate yields
(entries 5−9). Toluene was found to be the best solvent
among those screened, achieving a 78% yield (entry 10).
Further study of the lanthanide center of the catalyst was
then conducted. [(Me3Si)2N]3Ln(μ-Cl)Li(THF)3 with differ-
ent metal centers from La to Yb was evaluated, and all of the
reactions afforded the product in high yields (Table 2, entries
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a
a
Table 3. Ligand Screening
Scheme 2. Synthesis of Pyrano[2,3-b]indol-2-ones
entry
ligand
catalyst:L
yield (%)
1
2
3
4
5
6
7
8
−
50
48
59
59
67
54
56
62
54
45
42
58
45
55
57
69
72
85
84
88
85
58
67
67
65
4-(tert-butyl)phenol
2-(tert-butyl)phenol
2,6-di(tert-butyl)-4-methylphenol
1:3
1:3
1:1
1:3
1:1
1:3
1:1
1:1
1:1
1:3
1:1
1:3
1:1
1:3
1:1
1:3
1:1
1:3
1:1
1:3
1:1
1:3
1:1
1:3
L1
L2
L3
L4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
L5
b
L6
b
b
L7
b
b
L8
b
b
L9
b
b
L10
L11
b
b
b
a
Reaction conditions: 0.29 mmol of 1, 0.29 mmol of 2, 0.24 mmol of
3, 10 mol % [(Me3Si)2N]3La(μ-Cl)Li(THF)3 (relative to 3), 10 mol
% L9, 110 °C, 2.5 h, 1.0 mL of toluene. Isolated yields are reported.
a
Reaction conditions: 0.29 mmol of 1a, 0.29 mmol of 2, 0.24 mmol
of 3a, 10 mol % [(Me3Si)2N]3La(μ-Cl)Li(THF)3 (relative to 3a), 110
b
°C, 1.5 h, 1.0 mL of toluene. Isolated yields are reported. Reaction
time of 2.5 h.
substituted isatin. The latter gave a lower yield of 69% (4fa).
The reaction system was also found to be applicable to isatins
with substituents at each position of the benzene ring (1g−
1y). Cyclopropenones bearing different aryl groups at
positions 2 and 3 (3b−3d) were tried, and satisfactory yields
were obtained.
A scale-up experiment was performed to show the
practicability of this reaction system (Scheme 3), and product
4aa was obtained in 76% yield.
1,3-diphenylpropane-1,3-dione (L8 and L9) were synthesized
and added to the reaction mixtures (entries 18−21), resulting
in remarkably enhanced yields. Monoimines derived from 1,3-
diphenylpropane-1,3-dione (L10 and L11) did not exhibit
behaviors similar to those of β-diketimines (entries 22−25).
Accordingly, L9 at a catalyst:ligand ratio of 1:1 was chosen for
further reaction.
With the optimum reaction conditions in hand, the
generality of our method for the synthesis of pyrano[2,3-
b]indol-2-ones was investigated using structurally varied isatins
and cyclopropenones. The results are summarized in Scheme
2. Isatins with different substituents connected to the nitrogen
atom (1a−1e) all reacted well, except for the N-acetyl-
Considering the unique properties of lanthanide silylamides,
a plausible mechanism for this reaction is proposed (Scheme
4). First, diethyl phosphite goes through a rapid deprotonation
initiated by the lanthanide silylamide, generating catalytically
active species A. The central lanthanide ion of A then
coordinates to the ketone carbonyl moiety of the isatin, and a
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Scheme 3. Scale-up Experiment
Scheme 5. Mechanistic Investigation Experiments
Scheme 4. Proposed Reaction Mechanism
Pudovik reaction13 occurs to form intermediate B, which
undergoes rapid [1,2]-phospha-Brook rearrangement14 to
generate intermediate C. As the key intermediate of the
cycle, C abstracts the proton of the diethyl phosphite to
produce phosphate 5a and regenerate active species A to
accomplish the first catalytic cycle. Furthermore, C can attack
2,3-diphenylcyclopropenone through 1,4-addition followed by
a ring-opening process to generate intermediate D. Upon the
formation of D, another possible active species E may be
created. The proton exchange between 5a and E then releases
intermediate C again. Target product 4 can be obtained by
intramolecular cyclization of D. For further insight into the
role of ligand L9 in improving the catalytic activity, the L9−La
complex was synthesized by the treatment of L9 with
[(Me3Si)2N]3La(μ-Cl)Li(THF)3 in a molar ratio of 1:1 at 50
°C in THF. After evaporation of the solvent, a powder was
obtained and characterized by 1H NMR spectroscopy (see the
Supporting Information). The spectrum showed that the
central La atom bonds to two silylamides and one ligand, and
two tetrahydrofuran molecules are also coordinated to the
central metal. Due to the variation of the coordination
environment around the lanthanide metal center, the sterically
more crowded [La]−N(SiMe3)2 complex may undergo the
metathesis reaction with HOP(OEt)2 more rapidly to form
species A.
Then, 20 mol % E was added to the mixture of 5a and
diphenylcyclopropenone, and the reaction was carried out
under standard conditions (Scheme 5b). After workup,
product 4aa was obtained in 85% yield, confirming the role
of E in the process. In addition, 3-(1-ethyl-2-oxoindolin-3-
ylidene)-2,3-diphenylproanoic acid (6aa) was isolated in 8%
yield in addition to 4aa after a typical reaction process
(Scheme 5c), indicating the existence of intermediate D, which
serves as the precursor of 4aa. The structure of 6aa was
confirmed by X-ray crystallography.
In conclusion, we have developed a lanthanide silylamide-
catalyzed tandem reaction of isatins, diethyl phosphite, and
2,3-diarylcyclopropenones that provides a variety of pyrano-
[2,3-b]indol-2-ones in high yields. The high efficiency of the
lanthanide amide in catalyzing the reaction is the result of the
cooperation between the lanthanide metal center and the
N(SiMe3)2 anion. β-Diketimines derived from 1,3-diphenyl-
propane-1,3-dione were found to be valuable ligands for the
reaction. This method provides a simple and efficient synthetic
tool for the construction of pyrano[2,3-b]indole scaffolds.
To confirm this mechanism, several further experiments
were conducted. First, the reaction of N-ethyl isatin and diethyl
phosphite15 catalyzed by [(Me3Si)2N]3La(μ-Cl)Li(THF)3 was
carried out at room temperature for 0.5 h followed by the
addition of water (Scheme 5a). The expected product, diethyl
(1-ethyl-2-oxoindolin-3-yl)phosphate (5a), was obtained in
94% yield, indicating the generation of intermediate C. When
5a was mixed with 2,3-diphenylcyclopropenone in the
presence of 20 mol % [(Me3Si)2N]3La(μ-Cl)Li(THF)3
under typical reaction conditions, 4aa was obtained in 83%
yield. E was proposed as an active species formed during the
catalytic process. Accordingly, an in situ-formed E-catalyzed
reaction starting with 5a was conducted. Lanthanum
phosphate E was prepared by the metathesis reaction of
[(Me3Si)2N]3La(μ-Cl)Li(THF)3 and diethyl phosphate, the
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01506.
Experimental procedures, characterization data, NMR
spectra, and X-ray data for compounds 4aa and 6aa
(PDF)
Accession Codes
CCDC 2041573 and 2044799 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
1
structure of which was confirmed by H NMR detection.
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Letter
(10) For the recent representative literature, see: (a) Dicken, R. D.;
Motta, A.; Marks, T. J. Homoleptic Lanthanide Amide Catalysts for
Organic Synthesis: Experiment and Theory. ACS Catal. 2021, 11,
2715−2734. (b) Wang, F.; Wei, Y.; Wang, S.; Zhu, X.; Zhou, S.; Yang,
G.; Gu, X.; Zhang, G.; Mu, X. Synthesis, Characterization, and
Reactivity of Lanthanide Amides Incorporating Neutral Pyrrole
Ligand. Isolation and Characterization of Active Catalyst for
Cyanosilylation of Ketones. Organometallics 2015, 34, 86−93.
(c) Liu, P.; Chen, H.; Zhang, Y.; Xue, M.; Yao, Y.; Shen, Q.
Synthesis of γ-Amidine-functionalized Dianionic β-Diketiminato
Lanthanide Amides and Trianionic β-Diketiminato Na/Sm Hetero-
bimetallic Complexes and Their Reactivity in Polymerization of L-
Lactide. Dalton Trans. 2014, 43, 5586−5594. (d) Wu, Q.; Zhou, J.;
Yao, Z.; Xu, F.; Shen, Q. Lanthanide Amides [(Me3Si)2N]3Ln(μ-
Cl)Li(THF)3 Catalyzed Hydrophosphonylation of Aryl Aldehydes. J.
Org. Chem. 2010, 75, 7498−7501.
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Fan Xu − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P. R.
China; orcid.org/0000-0001-5914-8032; Email: xufan@
suda.edu.cn
Authors
Qifa Chen − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P.
R. China
Yue Teng − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, P.
R. China
(11) For the recent representative literature, see: (a) Nanda, T.;
Biswal, P.; Pati, B. V.; Banjare, S. K.; Ravikumar, P. C. Palladium-
Catalyzed C-C Bond Activation of Cyclopropenone: Modular Access
to Trisubstituted α,β-Unsaturated Esters and Amides. J. Org. Chem.
2021, 86, 2682−2695. (b) Wu, J.; Gao, W.; Huang, X.; Zhou, Y.; Liu,
M.; Wu, H. Selective [3 + 2] Cycloaddition of Cyclopropenone
Derivatives and Elemental Chalcogens. Org. Lett. 2020, 22, 5555−
5560. (c) Bai, D.; Yu, Y.; Guo, H.; Chang, J.; Li, X. Nickel(0)-
Catalyzed Enantioselective [3 + 2] Annulation of Cyclopropenones
and α,β-Unsaturated Ketones/Imines. Angew. Chem., Int. Ed. 2020,
59, 2740−2744. (d) Liu, Y.; Tian, Y.; Su, K.; Wang, P.; Guo, X.;
Chen, B. Rhodium(III)-Catalyzed [3 + 3] Annulation Reactions of N-
Nitrosoanilines and Cyclopropenones: an Approach to Functionalized
4-Quinolones. Org. Chem. Front. 2019, 6, 3973−3977. (e) Yang, Y.;
Zhang, Z.; Zhang, X.; Wang, D.; Wei, Y.; Shi, M. Lewis Base-
Catalyzed Reactions of Cyclopropenones: Novel Synthesis of Mono-
or Multi-substituted Allenic Esters. Chem. Commun. 2014, 50, 115−
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01506
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21272168) and the Natural Science
Foundation of the Jiangsu Higher Education Institutions of
China (18KJA150007).
́
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Lorente, P.; Sánchez-Andrada, P.; Berná, J.; Pastor, A.; Bautista, D.;
Jones, P. G. Synthesis and Molecular Structure of β-Phosphinoyl
Carboxamides: An Unexpected Case of Chiral Discrimination of
Hydrogen-Bonded Dimers in the Solid State. Chem. - Eur. J. 2010, 16,
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