Catalytic stereoselective synthesis of diverse oxindoles and spirooxindoles from isatins

Article abstract of DOI:10.1021/co300003c

A strategy for the efficient two-step synthesis of triazole derivatives of oxindoles and spirooxindoles is presented. Using a common set of N-propargylated isatins, a series of mechanistically distinct stereoselective reactions with different combinations

Full text of DOI:10.1021/co300003c

Research Article
pubs.acs.org/acscombsci
Catalytic Stereoselective Synthesis of Diverse Oxindoles and
Spirooxindoles from Isatins
Jacob P. MacDonald, Joseph J. Badillo, Gary E. Arevalo, Abel Silva-García, and Annaliese K. Franz*
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: A strategy for the efficient two-step synthesis of
triazole derivatives of oxindoles and spirooxindoles is presented.
Using a common set of N-propargylated isatins, a series of
mechanistically distinct stereoselective reactions with different
combinations of nucleophiles and catalysts provide access to
diverse hydroxy-oxindoles, spiroindolones, and spirocyclic oxazo-
line structures. The resulting N-propargylated oxindoles are then
converted to triazoles using copper-catalyzed azide−alkyne
cycloaddition (CuAAC) reactions. Overall, this strategy affords
a 64-member pilot-scale library of diverse oxindoles and
spirooxindoles.
KEYWORDS: heterocycles, isatins, oxindoles, spirooxindoles, spiroindolones, oxazolines, triazoles
inhibitor of SARS CoV 3C-like proteases.5 Initially driven by
efficient synthetic methods, the 1,2,3-triazole has now emerged
INTRODUCTION
Complex functionalized molecules are important compounds of
■
as a heterocycle of biological interest in drug discovery and
interest for biological probes and as new molecules for
medicinal chemistry programs.6,7 For example, triazole 2 shows
pharmaceutical lead discovery. Oxindole and spirooxindole
activity against tuberculosis strain H37RV.6b The significant
scaffolds have generated considerable synthetic interest due to
biological activities observed for oxindoles and triazoles
their occurrence in diverse natural products and notable
emphasizes the need to develop efficient synthetic strategies
biological activity.1,2 In a recent discovery, spiroindolone
to access these scaffolds and increase structural diversity for
NITD609 demonstrated nanomolar activity as a therapeutic
drug discovery and medicinal chemistry programs.
agent that kills the blood stage of Plasmodium falciparum and
Previous work from our laboratory has demonstrated several
has single-dose efficacy in a rodent malaria model (Figure 1).3
methods of catalytic activation of the isatin dicarbonyl for
Various hydroxy-oxindoles scaffolds also demonstrate impor-
efficient and selective nucleophilic additions and spirocycliza-
tant biological activity, such as Convolutamydine A, a natural
tions at the 3-position.8 The strategy we envisioned utilizes a
product with potent activity against leukemia cells.4 Substituted
isatin (indole-2,3-diones) scaffolds have also shown promising
examples of biological activity. For example, isatin 1 is a potent
common set of N-propargylated isatins 3 to access diverse
oxindole scaffolds through a series of mechanistically distinct
nucleophilic addition pathways. Each resulting oxindole scaffold
contains an alkyne group that provides further opportunities for
structural diversification with triazole heterocycles using the
copper-catalyzed azide−alkyne cycloaddition (CuAAC) reac-
tion. We also envisioned that the N-propargylated isatins 3
would be directly utilized in the CuAAC reaction as a fifth
scaffold because triazole-containing isatins have not previously
been reported or evaluated for biological activity. Here we
describe the realization of this strategy for rapid access (two
synthetic steps) to a pilot-scale library of diverse triazole-
containing hydroxy-oxindoles 4−6, spiroindolones 7, isatin-
triazoles 8, and spirooxazolines 9 and 10 emanating from a
common set of propargylated isatins 3 (Scheme 1). Overall, our
two-step strategy affords a library of 64 oxindole and
Received: January 9, 2012
Revised: March 19, 2012
Published: March 26, 2012
Figure 1. Biologically active oxindoles and triazoles.
© 2012 American Chemical Society
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ACS Combinatorial Science
Research Article
Scheme 1. Outline of Synthetic Strategy towards Substituted Triazole-Containing Oxindoles
Scheme 2. Nucleophilic Addition Reactions to Access Oxindoles and Spirooxindoles
spirooxindole compounds, including 15 core scaffolds and 49
triazole derivatives. The efficient stereoselective syntheses of
complex heterocycles combining both oxindole and triazole
motifs have not been described previously. On the basis of the
breadth of biological activity known for isatins, oxindoles and
spirooxindoles, these densely functionalized heterocycles
should serve as important biological probes for chemical
biology.
RESULTS AND DISCUSSION
■
A key feature in this strategy is the regio-, diastereo- and
enantioselective synthesis of the oxindole and spirooxindole
scaffolds (Scheme 2). On the basis of the nucleophile
component (11) utilized (Scheme 1), four oxindole scaffolds
were selected for this library: hydroxy-oxindoles 13−15 are
prepared enantioselectively using a chiral Lewis acid catalyst
(19);8b spiroindolones 16 are prepared enantioselectively using
a chiral Bronsted acid catalyst (20);8c and the 2-oxazoline and
̈
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Table 1. Enantioselective Synthesis of Substituted Hydroxy−Oxindole Scaffolds
a
b
entry
R
isatin
nucleophile
product
yield
%ee
c
1
5-F
3b
3b
3b
3c
3c
3c
11a
11b
11c
11a
11b
11c
13b
14b
15b
13c
14c
15c
97
79
97
78
90
97
98
87
96
86
94
99
d
2
5-F
3
5-F
c
4
d
4-Cl
4-Cl
4-Cl
5
6
a
b
c
d
Isolated yields. Determined using HPLC analysis with chiral stationary phase. Reaction performed at −20 °C. Reaction was performed using 3.0
equiv of TMSCl and 0.1 equiv of NaSbF6 in MeCN.
Table 2. Enantioselective Synthesis of Spiroindolone Scaffolds
a
b
entry
R
isatin
product
catalyst
yield (%)
%ee
c
1
2
3
H
3a
3b
3f
16a
16b
16f
Sc(OTf)3
89
5-F
7-F
20
86
c
84
d
thiourea
92
a
b
c
d
Isolated yield. Determined using HPLC analysis with chiral stationary phase. Reaction was performed in DCM solvent. Thiourea = 1,3-bis(3,5-
bis(trifluoromethyl)-phenyl)thiourea.
Table 3. Regio- and Stereoselective Spirocyclization to Afford 2- and 3-Spirooxazoline Scaffolds
a
b
entry
R
isatin
oxazole
product
yield (%)
dr
c
1
2
3
4
5
6
5-F
4-Cl
H
3b
3c
3a
3b
3c
3d
11e
11e
11f
11f
11f
11f
17b
17c
18a
18b
18c
18d
55
90:10
99:1
90:10
93:7
95:5
99:1
74
c
77
5-F
4-Cl
5-Br
87
c
51
95
a
b
c
Isolated yield of major diastereomer. Determined by analysis of 1H NMR spectroscopy of crude reaction mixture. Yields sacrificed for purity due
to the presence of byproduct which proved to be difficult to separate by column chromatography (conversion ≥80% by TLC).
3-oxazoline spirocycles 17 and 18 are each prepared diastereo-
and regioselectively using a titanium(IV) Lewis acid catalyst
(Scheme 2).8a For some scaffolds, isatins (3) are selected on
the basis substitution patterns that ensure high selectivity.
First, a series of 3-substituted-3-hydroxy-oxindole scaffolds
13−15 were accessed using scandium(III)-catalyzed enantio-
selective additions with representative π-nucleophiles: N-
methylindole (11a), 2-methallylsilane (11b), and N,N-
dimethyl-m-anisidine (11c).8b Scandium(III) complexes
formed with the 2,6-bis[(3aS,8aR)-3a,8a-dihydro-8H-indeno-
[1,2-d]oxazolin-2yl]pyridine ligand (e.g., 19) are known to be
effective chiral Lewis acid catalysts with good chelating
potential.9 As outlined in Table 1, isatins 3b−c were utilized
to afford hydroxy oxindoles 13−15 with high yields (78−97%)
and enantioselectivity (85−99% ee). All reactions were
performed at room temperature, with the exception of entries
1 and 4, which were performed at −20 °C because of the high
reactivity of the nucleophile. In the case of the methallylsilane
(11b, entries 2 and 5), the reaction is run in acetonitrile with
TMSCl and NaSbF6 as additives to increase the efficiency of
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Research Article
the reaction and promote in situ deprotection of any resulting
OTMS product so that the hydroxy-oxindole products 13−15
are obtained exclusively.10,11
Scheme 3. Methods Compared for the Synthesis of Triazoles
with Propargylated Isatins
Using an asymmetric Pictet−Spengler-type spirocyclization
reaction,12 three spiroindolone scaffolds were prepared upon
acid-catalyzed spirocyclization of 5-methoxytryptamine (11d)
with isatins (Table 2).8c,13 We have previously shown that this
reaction is efficiently catalyzed using Lewis acidic metal salts,
thioureas, or BINOL-derived chiral phosphoric acids. The 5-
fluorospiroindolone 16b was prepared using a BINOL-derived
phosphoric acid catalyst to demonstrate the enantioselective
synthesis and evaluate the retention of enantiomeric excess in
the CuAAC reaction. Using (S)-3,3′-bis(2,4,6-triisopropylphen-
yl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (20) as the
catalyst, fluorospiroindolone 16b was attained in excellent yield
(86%) and high enantioselectivity (84% ee) (Table 2, entry
2).11 Using either Sc(OTf)3 or 1,3-bis(3,5-bis(trifluoromethyl)-
phenyl)thiourea provides an efficient (and less expensive)
catalyst for the preparation of racemic spiroindolones (Table 2,
entries 1 and 3). Isatins 3b and 3f were selected due to the
therapeutic relevance of fluorinated molecules as well as the
efficient performance of these isatins in the Pictet−Spengler
reaction.3b,14
A series of spirooxindole oxazoline scaffolds were prepared
using the titanium(IV)-catalyzed regio- and diastereoselective
addition and spirocyclization of 5-methoxyoxazoles to
isatins.8a,15 Substitution at the 4-position of the oxazole
controls the regiochemistry, with the 4-isopropyloxazole (11f)
giving rise to the 3-oxazoline scaffold 18 and the 4-H oxazole
(11e) leading to the 2-oxazoline scaffold 17.8a,11,16 In general,
the oxazole addition to propargyl isatins 3a−d proceeded with
high regio- and diastereoselectivity (>99% rr, up to 99% dr)
and in high yields (up to 95%); however, in two cases (17b and
18c) the isolated yield was low because of the presence of
byproduct that proved to be difficult to separate by column
chromatography. All reactions proceed with high diastereose-
lectivity, but the 4-chloroisatin 3c is particularly effective for
dictating high diastereoselectivity in the formation of 2-
oxazolines, such as 17c.
Triazole Synthesis. This collection of diverse oxindole and
spirooxindole scaffolds contains a common feature through the
N-propargyl group of each scaffold, which can be further
diversified using azide−alkyne cycloaddition chemistry. We set
out to compare several variations of CuAAC reactions for this
collection of N-propargylated oxindoles. We began by exploring
one-pot reaction conditions that utilize in situ generated azides,
prepared from the corresponding amine using the shelf-stable
diazotransfer reagent 1H-imidazole-1-sulfonyl azide (21)
(Scheme 3, eq 1).17 Unfortunately, this method did not work
for these oxindole substrates due to side reactions and
decomposition of starting material under the diazo transfer
conditions. Several solvent combinations (THF, MeOH/THF,
DCM), copper reagents, and conditions (i.e., Cu(I) vs Cu(II)
reduction by sodium ascorbate in situ) were explored, but only
minimal triazole formation was observed for the one-pot
procedure. Next, we investigated a route utilizing in situ
generated aryl azides prepared from commercially available aryl
iodides with sodium azide in the presence of copper iodide
(Scheme 3, eq 2).18 This method was also considered to be
attractive because it provides access to diverse aryl triazoles,
including amino-substituted triazoles that are not available
when preparing azides from amines. This method has
previously only been reported for less-functionalized substrates,
but here the conditions generally afforded low yields (33−40%)
for the more complex oxindole substrates. Low yields are
attributed to the formation of undesired polymeric-side
products.
Ultimately, we utilized a method applicable for the synthesis
of both alkyl- and aryl-substituted triazoles using purified azides
that were prepared in one-step from the corresponding amine
and diazotransfer reagent 21 (Table 4).19 Azides 12a-f were
selected to include indolyl, pyridyl, ester, and phenyl derivatives
in order to provide a variation in molecular weights, hydrogen
bonding donor and acceptor properties, and capabilities for π-
interactions. Azides 12a−e were each prepared from the amine
using diazotransfer reagent 21, and azide 12f was prepared by
direct displacement of a chloride with sodium azide.20 After
purification and isolation, azides 12a−f were then allowed to
react directly with the N-propargyl-oxindoles or spirooxindoles
in the presence of catalytic Cu(I) iodide (10 mol %) and di-
isopropylethylamine (15 mol %) in THF to afford triazoles 4−
10.21 A representative combination of N-propargyl-oxindole
scaffolds and azide components were evaluated to ascertain the
scope of compounds accessible using this strategy (Scheme 1).
Overall, these reactions proceeded with high yields (>70%) for
36 of 45 triazoles prepared, and only 8 of the 45 reactions
afforded less than 66% yield (Table 4). These low yields are
attributed to lower conversion and unreacted starting material
for the given reaction time. Of practical consideration, the
CuAAC reactions of isatins (entries 20−27) proceeded with
excellent yields and were particularly clean and easy to purify.
Examples of representative final oxindole and spirooxindole
products are shown in Figure 2.
Because hydroxy-oxindoles 13−15 were prepared as
enantiomerically enriched compounds using asymmetric
catalysis, it is especially important to demonstrate that the
enantiomeric excess of these compounds was maintained
during the CuAAC reaction since these compounds are
known to form stabilized carbocations under metal- and acid-
catalyzed conditions.22 The enantiomerically enriched N-
propargylated 3-hydroxy-oxindoles were subjected to the
CuAAC conditions with azides 12a−c (Table 4, entries 1−
14). The enantiomeric excess of the triazole-containing 3-
hydroxy-3-indolyl-oxindole 4ba was confirmed by HPLC
analysis using chiral stationary phase by comparison to the
triazoles produced by racemic synthesis.23 Due to the similarity
of hydroxy-oxindoles 13−15, the retention of enantiomeric
excess for 4ba was used as a model for retention of
enantioselectivity for all triazole products. Enantiomerically
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Table 4. Synthesis of Triazole-Functionalized Isatins, Oxindoles, and Spirooxindoles
a
b
entry
R
isatin/oxindole
azide (R1)
product
yield (%)
1
5-F
13b
13b
13b
14b
14b
15b
15b
13c
13c
14c
14c
15c
15c
15c
16a
16a
16b
16b
16f
3a
12a
12b
12c
12a
12b
12a
12b
12a
12b
12a
12b
12a
12b
12c
12c
12f
4ba
4bb
4bc
5ba
5bb
6ba
6bb
4ca
78
80
99
64
71
56
99
40
70
94
58
91
94
58
95
95
62
97
70
69
99
95
55
99
97
74
99
74
88
94
88
87
99
92
76
70
90
80
74
70
94
74
66
93
99
2
5-F
5-F
5-F
5-F
5-F
5-F
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
3
4
5
6
7
8
9
4cb
5ca
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
5cb
6ca
6cb
6cc
7ac
H
7af
5-F
5-F
7-F
H
12b
12c
12a
12d
12a
12e
12a
12f
7bb
7bc
7fa
8ad
8aa
H
3a
H
3a
8ae
4-Cl
4-Cl
4-Cl
5-Br
5-OMe
5-F
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
3c
8ca
3c
8cf
3c
12c
12a
12a
12b
12a
12b
12c
12f
8cc
3d
8da
8ea
3e
17b
17c
17c
17c
17c
17c
18a
18a
18a
18a
18b
18b
18b
18b
18b
18c
18c
18d
9bb
9ca
9cb
9cc
9cf
12d
12a
12b
12f
9cd
10aa
10ab
10af
10ad
10ba
10bb
10bc
10be
10bd
10cb
10cd
10da
H
H
H
12d
12a
12b
12c
12e
12d
12b
12d
12a
5-F
5-F
5-F
5-F
5-F
4-Cl
4-Cl
5-Br
a
b
All reactions performed with CuI (10 mol %) and DIPEA (15 mol %) in THF from 12 to 24 h. Isolated yield.
enriched spiroindolone 16b was used to demonstrate that the
enantiomeric excess for this class of spirooxindoles is retained
under CuAAC reaction conditions (entry 17).
The spirocyclic oxazolines 17 and 18 afforded spirocyclic
triazoles 9 and 10 in excellent yields (Table 4, entries 28−45);
however, the reversed order of the reaction sequence was also
investigated. For spirooxazoline-triazole 9, the titanium(IV)-
catalyzed addition and spirocyclization of 5-methoxyoxazole
11e can also be performed using a triazole-containing isatin
(derived from azide 12a) in 71% yield and maintaining high
diastereoselectivity (97:3 dr). However, the success of the
spirocyclization is dependent on the nature of the triazole
substrate (see Supporting Information). Although the reaction
proceeded successfully with the isatin triazole derived from p-
methoxy phenyl azide 12a, the use of an isatin triazole derived
from azide 12b did not undergo spirocyclization, presumably
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Figure 2. Representative final oxindole and spirooxindole products.
Table 5. Synthesis of Triazole-Functionalized Oxindoles and Isatins from Aryl-iodides
a
b
entry
R1
isatin/oxindole
Ar−N3
product
yield (%)
c
1
4-Cl
5-OMe
5-F
3c
12g
12h
12i
12i
12i
8ca
8eh
5bi
5ci
6ci
23
35
28
40
19
c
2
3e
d
3
14b
14c
d
4
4-Cl
4-Cl
d
5
15c
a
b
c
Azide generated in situ from the corresponding aryl-iodide. Isolated yield. Reactions performed using CuI (10 mol %), and DMEDA (15 mol %)
d
according to Scheme 3, eq 3. Reaction performed with 1 equiv of CuSO4·5H2O, and 1.1 equiv of sodium ascorbate.
due to interactions between the indole ring and the titanium
catalyst.
copper, also affording low yields of the triazole products. When
the amount of copper was increased to stoichiometric amounts,
several unidentified side-products were formed and the increase
in yield was negligible. In order to reduce the amount of side
products and increase yields, conditions were modified to use a
stoichiometric amount of copper(II) reagent with sodium
ascorbate to generate the catalytic Cu(I) species in situ. Even
with these optimized conditions, the yield of pyridinyl triazoles
remained low (Table 5, entries 3−5). This result is in contrast
to the reaction of pyridyl azide 12e, which was successfully
utilized and afforded triazole products with excellent yields
(Table 4, entries 22 and 41). However, this method can provide
additional interesting compounds for biological screening.
An analysis of the molecular properties and shape for this
collection of oxindole compounds indicates desirable properties
Although our earlier investigations had shown that the one-
pot reaction using aryl iodides proceeded with low yield, we
briefly explored this approach to incorporate additional triazole
diversity (Table 5). For example, this one-pot method allows
the synthesis of triazole isatin 8eh containing an amino group,
which cannot be accessed with the previous route described
above (Table 4). This CuAAC strategy uses 10 mol % of CuI
and 15 mol % of DMEDA with one equivalent of aryl-iodide
and one equivalent of the alkyne in DMF.18 Triazoles 8ca and
8eh were obtained when isatins 3c,e were subjected to the
reaction with aryl-iodides; however, low yields were observed
(Table 5, entries 1−2). Similarly, with hydroxy-oxindoles 14
and 15, the reaction was sluggish with catalytic amounts of
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and diversity for high-throughput screening and the discovery
of pharmaceutical leads or biological probes. Molecular
properties for all compounds were calculated (see Supporting
Information) and a summary of the average values are provided
in Table 6. The majority of compounds and average values are
mol from the minimum energy conformer are represented. This
shape analysis also includes the structures of the known
biologically active compounds in Figure 1 for comparison.
In conclusion, we have developed an efficient enantio- and
diastereoselective synthetic strategy to access a diverse 64-
compound pilot-scale library including 15 oxindole scaffolds
and 49 triazole containing-oxindoles and isatins. We demon-
strate that enantiomeric excess resulting from the catalytic
asymmetric synthesis of oxindoles and spirooxindoles is
retained upon further functionalization with the CuAAC
reaction, thus providing efficient methods to prepare libraries
of enantiomerically enriched spirocyclic compounds. The
nucleophile and azide building blocks selected here afford a
collection of compounds with diversity that is appropriate for
high-throughput screening and the discovery of pharmaceutical
leads or biological probes. All of the compounds in this report
have been submitted to the NIH Molecular Libraries Small
Molecule Repository for biological screening.
Table 6. Average values of Molecular Properties
oxindole cores
isatin triazoles
oxindole triazoles
property
MW
(n = 15)
(n = 9)
(n = 40)
399
3
353
2
551
3
a
XLogP
b
TPSA
67
4
81
4
109
8
rotatable
bonds
HBA
3
1
2
4
0
3
5
1
4
HBD
no. of rings
a
XLogP is used for the calculated partition coefficients (cLogP) values
b
based on the method of Wang, see ref 25. Topological Polar Surface
ASSOCIATED CONTENT
* Supporting Information
Complete characterization data for 27 compounds, including
Area (TPSA) based on the method of Ertl, see ref 28.
■
S
within accepted ranges for the development of lead
compounds.24 The nucleophile and azide building blocks
selected here afford a collection of compounds with molecular
weights ranging from 259 to 721, and calculated partition
coefficients (cLogP) values with a range of 0.56 to 5.38, based
on the XLogP method of Wang.25 The molecular weights span
a range that includes molecular weights appropriate for lead-like
molecules, as well as access to higher molecular weight
compounds, which could prove useful as biological probes for
the disruption of protein−protein interactions.26 In order to
visualize the molecular shape diversity, we generated a scatter
plot based on the principal moments of inertia (PMI) ratios
(Figure 3), a method developed by Sauer and Schwarz.27 This
method classifies the molecular shape into three categories: rod
(acetylene), disk (benzene), or spherical (adamantane). Since
several conformations of a compound are capable of binding to
a biological target, a collection of 3D-conformations ≤3 kcal/
1
HPLC data for enantioenriched compounds; H NMR spectra
and mass spectrometry data available for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: akfranz@ucdavis.edu.
■
Author Contributions
A.K.F. conceived the strategy and experiments; J.P.M., J.J.B.,
G.E.A., and A.S. designed and performed the experiments;
A.K.F. and J.P.M. cowrote the manuscript; J.P.M. and J.J.B.
cowrote the Supporting Information.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NIH/NIGMS (P41-GM0891583).
A.K.F. acknowledges 3M Corporation for a Nontenured
Faculty Award. J.J.B. acknowledges support from the National
Science Foundation in the form of a graduate research
fellowship; A.S. would like to thank Bristol-Myers Squibb for
an undergraduate research fellowship.
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