Palladium-Catalyzed Ligand-Free Double Cyclization Reactions for the Synthesis of 3-(1′-Indolyl)-phthalides

Article abstract of DOI:10.1021/acs.orglett.9b04241

Indole and phthalide are privileged heterocyclic scaffolds in numerous natural products and bioactive molecules. The synthesis and biological evaluation of the compounds combining these two scaffolds have rarely been reported. Herein, we repot the first palladium-catalyzed ligand-free double cyclization reactions that enable efficient synthesis of 3-(1′-indolyl)-phthalides (42 examples, up to 96% yield) under mild conditions. Notably, only 1.0 mol % of catalyst loading is used, suggesting high efficiency. Late-stage elaborations give highly functionalized analogues.

Full text of DOI:10.1021/acs.orglett.9b04241

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Letter
Palladium-Catalyzed Ligand-Free Double Cyclization Reactions for
the Synthesis of 3‑(1′-Indolyl)-phthalides
Shuo Yuan, Dan-Qing Zhang, Jing-Ya Zhang, Bin Yu,* and Hong-Min Liu*
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ABSTRACT: Indole and phthalide are privileged heterocyclic
scaffolds in numerous natural products and bioactive molecules. The
synthesis and biological evaluation of the compounds combining these
two scaffolds have rarely been reported. Herein, we repot the first
palladium-catalyzed ligand-free double cyclization reactions that enable
efficient synthesis of 3-(1′-indolyl)-phthalides (42 examples, up to 96%
yield) under mild conditions. Notably, only 1.0 mol % of catalyst
loading is used, suggesting high efficiency. Late-stage elaborations give
highly functionalized analogues.
he privileged heterocyclic indole and phthalide scaffolds
widely exist in natural products (NPs) and pharmaceut-
to their diverse and interesting biological profiles of indoles
and phthalides, compounds combining the indole and
phthalide moieties may have potential biological activities.
Very recently, Hasbullah et al. preliminarily revealed that the
phthalide-fused indoles were cytotoxic against HL-60 and
HepG2 cells.12 Of note, the syntheses of compounds
containing indole and phthalide moieties have not been
extensively explored, and very few approaches have been
documented in the literature, thus limiting further biological
evaluation of such compounds. In 1960, Johnson et al.
achieved the first synthesis of substituted 3-(indolyl)-
phthalides from 2-formylbenzoic acid and indole substrates;
the types of products depended on the substitution pattern of
indole substrates; and the reactions were performed at high
temperatures (up to 270 °C) (Scheme 1A).13 Until recently,
another two groups independently reported the synthesis of 3-
(indolyl)-phthalides under microwave or aqueous conditions
(Scheme 1B).12,14
T
icals, and such compounds have proven to possess a wide
variety of pharmacological properties, such as anti-inflamma-
tory, anticancer, and antinociception.1−5 Representative
indole-containing examples are Hippadine (lycorine-type
alkaloids found in the bulbs),6 Psilocin (a substituted
tryptamine alkaloid with serotonergic psychedelic activity),7
and (−)-Aurantioclavine (isolated from Penicillium aurantio-
virens and as an intermediate for the synthesis of polycyclic
alkaloids of the communesin family)8 (Figure 1A). In addition,
Evidently, these approaches relied on indole substrates, and
the appendage diversity of the products only depends on the
substituents attached to the indole core. Therefore, the
efficient syntheses of compounds containing indole and
phthalide moieties are greatly needed. We believe that use of
different starting materials could achieve the diversity of this
focused library. Herein, we reported the first Pd-catalyzed
ligand-free double cyclization reactions for the synthesis of new
3-(1′-indolyl)-phthalides from 2-formylbenzoic acid and 2-
ethynylaniline, in which one C−O bond, two C−N bonds, one
indole, and one phthalide were formed simultaneously
Figure 1. Design of structurally rare 3-(1′-indolyl)-phthalides. (A)
Indole-containing NPs. (B) Phthalide-containing NPs.
phthalide fragments are also prevalent in natural products and
biologically active compounds,4 such as Noscapine (a
benzylisoquinoline alkaloid isolated from plants of the poppy
family),9 Epicoccone (a subgroup of polyphenols isolated from
Aspergillus flavipes with free radical scavenging activity),10 and
Senkyunolide B (one of the flavor constituents of celery oil
with potent spasmolysis of smooth muscle)11 (Figure 1B). Due
Received: November 26, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04241
© XXXX American Chemical Society
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A

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a
Scheme 1. Previously Reported Approaches for the
Construction of 3-(Indolyl)-phthalides and the Approach
Presented in This Work
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
solvent
T (°C) ratio (1a:2a)
3 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(acac)2
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2(dppf)
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
DMF
100
80
100
60
1:1
1:1
1:1
1:1
1:1
1:1
1:1.5
1:3
34
MeCN
DMSO
MeOH
H2O
52
53
55
13
73
93
94
58
100
100
100
100
100
100
100
100
100
100
100
rt
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
c
1.5:1
d
e
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
92 (90 )
42
39
22
48
29
46
63
c
c
c
c
c
c
c
60
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), palladium catalyst
b
1
(10 mol %), solvent (1 mL), 6 h. NMR yields determined by H
NMR using the triphenylmethane as an internal standard. 1.5 mmol
of 1a was used. 1.0 mol % of catalyst was used. Isolated yield.
c
d
e
(Scheme 1C). Compared to previously reported methods, this
protocol generated a series of 3-(indolyl)-phthalide derivatives
in excellent yields (42 examples, up to 96% yield). This
protocol was ligand-free and could be performed on a gram
scale. Notably, only 1.0 mol % of catalyst loading was used in
these reactions, indicating high efficiency and practicality.
Initially, 2-ethynylaniline 1a (1.0 mmol) and 2-formylben-
zoic acid 2a (1.0 mmol) were used as model substrates to
examine the scope of this transformation in the presence of 10
mol % of Pd(OAc)2 (Table 1). Compound 3 was obtained in
34% yield when the reaction was performed in DMF (Table 1,
entry 1). Encouraged by this result, we further examined the
reactivity in other solvents (Table 1, entries 2−6). To our
delight, compound 3 was generated in 73% yield when the
reaction was carried out in toluene (Table 1, entry 6). Other
solvents such as MeCN, DMSO, MeOH, and H2O turned out
to be less efficient, and compound 3 was afforded in relatively
lower yields (Table 1, entries 2−5). Next, we examined the
effects of different ratios of substrates on the reactivity (Table
1, entries 7−9). Compound 3 was obtained in 93% and 94%
yield, respectively, when 1.5 and 3.0 equiv of 2a was used
(Table 1, entries 7 and 8), about 20% higher than that when
1.0 equiv of 2a was used (Table 1, entry 6). Besides,
compound 3 was afforded in only 58% yield when 1.5 equiv of
1a was utilized (Table 1, entry 9). Intriguingly, when 1 mol %
of catalyst (Pd(OAc)2) loading was employed, the desired
product 3 was obtained in 92% yield, comparable to that in the
presence of 10 mol % of Pd(OAc)2 (Table 1, entry 10). Other
palladium catalysts such as Pd(acac)2, Pd(PPh3)4,
PdCl2(PPh3)2, PdCl2(dppf), and Pd2(dba)3 were less efficient
and delivered the desired compound in <50% yield (Table 1,
entries 11−15). Unfortunately, when the reactions were
conducted at lower temperatures, the product 3 was afforded
in 46% and 63% yield, respectively (Table 1, entries 16 and
17). According to the above optimizations, the optimal
reaction condition was 2-ethynylaniline (1.0 mmol), 2-
formylbenzoic acid (1.5 mmol), Pd(OAc)2 (1.0 mol %), and
toluene (1 mL), at 100 °C for 6 h (Table 1, entry 10).
With the optimized reaction conditions in hand, we next
examined the scope of 2-ethynylanilines and 2-formylbenzoic
acids (Scheme 2). As shown in Scheme 2, compounds 3−31
were obtained in moderate to excellent yields (66−96%)
regardless of their substitution patterns and electronic nature,
and various R1 substitutions attached to the phenyl ring were
well tolerated in these reactions. When R1 was halogen, the
corresponding products 4−9 were generated in good yields
(79−92%), which could be used for further functionalization.
Delightfully, both electron-deficient (substituted with −CF3,
−CN, −OCF3, −NO2, −COMe, −COOMe) and electron-rich
(substituted with alkyl, −OMe, −OEt, −Ph) 2-ethynylanilines
proceeded well under the optmized conditions and furnished
the compounds 10−27 in moderate to excellent yields (66−
96%). Interestingly, compounds 28−31 bearing the alkyl
groups were also formed in moderate yields (71−79%). For 5-
chloro-2-formylbenzoic acid, its corresponding product 32 was
obtained in 83% yield, comparable to that of compound 3. For
anilines bearing additional substituents, the corresponding
products 33−44 were formed in moderate to good yields (66−
91%). Finally, 2-ethynylaniline 1a (5 mmol) and 2-
formylbenzoic acid 2a (7.5 mmol) were employed to examine
the scability. To our delight, the desired product 3 was formed
in 85% yield under the standard reaction conditions. Among
these 3-(indolyl)-phthalides, X-ray crystallographic study was
performed and further confirmed the structure of compound 3
(CCDC number: 1886364). It is worth noting that only 3-(1′-
indolyl)-phthalides were afforded exclusively under the optimal
conditions, and the 3-(3′-indolyl)-phthalides were not
observed in these reactions.
To showcase the synthetic utilities, compound 3 was used
for late-stage diversification (Scheme 3). As shown in Scheme
B
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a
a
Scheme 2. Scope of 2-Ethynylanilines
Scheme 3. Late-Stage Elaborations
a
(A) Aniline (1 equiv), AcOH. (B) 2-Phenylacetaldehyde (1.1 equiv),
FeCl3·6H2O (2.5 mol %), EtOH (2.2 equiv), DCM. (C) NaIO4 (1
equiv), RuCl3·3H2O (5 mol %), MeCN. (D) t-BuOK (1 equiv), THF.
(E) Et2AlCl (1.5 equiv), acetyl chloride (1.2 equiv), DCM. (F) NaI
(1 equiv), PhI(OAc)2, MeCN:H2O (1:1).
examples regarding the late-stage elaboration of 3-(1′-indolyl)-
phthalides. Conceivably, more transformations could happen
starting from 3-(1′-indolyl)-phthalides, generating a diverse
compound library for biological testing.
Based on these results, the proposed mechanism for the
synthesis of 3-(1′-indolyl)-phthalides is depicted in Scheme 4.
Scheme 4. Proposed Reaction Mechanism for the
Formation of 3-(1′-Indolyl)-phthalides
a
Conditions: 1 (1 mmol), 2 (1.5 mmol), Pd(OAc)2 (1 mol %),
b
toluene (1 mL), 100 °C, 6 h. 1a (5 mmol), 2a (7.5 mmol),
Pd(OAc)2 (1 mol %), toluene (10 mL), 100 °C, 6 h.
3A, compound 3 reacted smoothly with aniline, giving
compound 45 in 61% yield. In the presence of FeCl3·6H2O,
dehydration reaction between compound 3 and 2-phenyl-
acetaldehyde afforded alkenylated compound 46 in 43% yield
(Scheme 3B). Oxidation of compound 3 with RuCl3·3H2O
yielded compound 47 in 70% yield (Scheme 3C). Treatment
of 3 with t-BuOK led to the C−N bond cleavage, yielding
compound 48 in 76% yield (Scheme 3D). We proposed that
the phthalide ring could be used as a new protecting group for
indole substrates and could be removed under mild conditions.
Friedel−Crafts acetylation of compound 3 with acetyl chloride
with the assistance of Et2AlCl gave the acylated compound 49
in 71% yield, and the acetyl group could be used for further
transformations (Scheme 3E). Iodination reaction of 3 with
NaI yielded the C-3 iodinated product 50 in quantitative yield
(Scheme 3F), which could be employed for building 3-
(indolyl)-phthalide collections. Presented here are just a few
Initially, the intermediate A, generated in situ from substrates
1a and 2a through the condensation reaction, coordinated with
Pd(OAc)2 to form complex B. Protonation exchange gave the
activated imine C, which promoted further intramolecular
cyclization and transmetalation to generate the complex D.
Further 5-endo N-cyclization transformation of complex D
afforded the product 3 and released the palladium catalyst.
Through the palladium-catalyzed cascade reactions, the new 3-
(1′-indolyl)-phthalide framework was efficiently constructed,
in which one C−O bond and two C−N bonds were formed
C
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simultaneously. Another possible pathway was that 2-
ethynylaniline first generated the 2-aryl indole under the
optimized reaction conditions, and the NH group of the 2-aryl
indole attacked the aldehyde group of 2-formylbenzoic acid,
followed by intramolecular dehydration reaction, finally
yielding the desirable products. To prove this possible
pathway, we tested the reactivity between 2-aryl indole and
2-formylbenzoic acid under the optimized conditions.
However, no desirable product was formed, thus excluding
this possibility.
In conclusion, we have developed the first palladium-
catalyzed ligand-free double cyclization reactions that enable
efficient synthesis of structurally novel and biologically
interesting 3-(1′-indolyl)-phthalides (42 examples, up to 96%
yield) under mild conditions, regardless of their attached
substituents. Of note, only 1.0 mol % of catalyst loading was
used in these reactions, and high reactivity (85% yield) was
also observed when the reaction was performed on a gram
scale (5.0 mmol). Through the palladium-catalyzed cascade
reactions, the 3-(1′-indolyl)-phthalide framework was effi-
ciently accessed, in which one C−O bond and two C−N
bonds were formed simultaneously. Late-stage elaborations
based on the 3-(1′-indolyl)-phthalide scaffold were carried out,
giving highly functionalized analogues, which could be
potentially used for construction of a diverse compound
library. Relative to previous methods, the protocol presented
here has several advantages such as mild reaction conditions,
low catalyst loading, and ligand free and more importantly
achieves greater appendage diversity.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04241
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 81773562, 81703326, and
81973177) and China Postdoctoral Science Foundation
(Nos. 2018M630840 and 2019T120641). We sincerely thank
Dr. Jinjun Shao (Nanjing Tech University) for performing the
high-temperature NMR analysis of compound 3.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04241.
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Experimental procedures, characterization data, and H
NMR and 13C NMR spectra for new compounds (PDF)
Accession Codes
CCDC 1886364 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Bin Yu − Zhengzhou University, Zhengzhou, China;
orcid.org/0000-0002-7207-643X; Email: yubin@
zzu.edu.cn
Hong-Min Liu − Zhengzhou University, Zhengzhou,
China; orcid.org/0000-0001-6771-9421;
Email: liuhm@zzu.edu.cn
Other Authors
Shuo Yuan − Zhengzhou University, Zhengzhou, China;
orcid.org/0000-0002-4273-5625
Dan-Qing Zhang − Zhengzhou University, Zhengzhou,
China
Jing-Ya Zhang − Zhengzhou University, Zhengzhou,
China
D
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Org. Lett. XXXX, XXX, XXX−XXX