Gold-catalyzed 5-endo-dig cyclization of 2-[(2-aminophenyl)ethynyl] phenylamine with ketones for the synthesis of spiroindolone and indolo[3,2-c]quinolone scaffolds

Article abstract of DOI:10.1002/ejoc.201402006

A tandem gold-catalyzed 5-endo-dig/spirocyclization of 2-[(2-aminophenyl) ethynyl]phenylamines with isatins was achieved to produce the corresponding 5′,11′-dihydrospiro[indoline-3,6′-indolo[3,2-c]quinolin] -2-one derivatives in good yields with high regioselectivity. This reaction proceeded well at ambient temperature under mild conditions. Ketones also participated smoothly under similar conditions to produce 6,6-disubstituted-6, 11-dihydro-5H-indolo[3,2-c]quinolones. Copyright

Full text of DOI:10.1002/ejoc.201402006

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402006
Gold-Catalyzed 5-endo-dig Cyclization of 2-[(2-Aminophenyl)-
ethynyl]phenylamine with Ketones for the Synthesis of Spiroindolone and
Indolo[3,2-c]quinolone Scaffolds
Basi. V. Subba Reddy,*[a] Manisha Swain,[a] S. Madhusudana Reddy,[a] J. S. Yadav,[a] and
B. Sridhar[b]
Keywords: Amines / Domino reactions / Gold / Nitrogen heterocycles / Spiro compounds
A tandem gold-catalyzed 5-endo-dig/spirocyclization of 2-
[(2-aminophenyl)ethynyl]phenylamines with isatins was
achieved to produce the corresponding 5Ј,11Ј-dihydrospiro-
[indoline-3,6Ј-indolo[3,2-c]quinolin]-2-one derivatives in
good yields with high regioselectivity. This reaction pro-
ceeded well at ambient temperature under mild conditions.
Ketones also participated smoothly under similar conditions
to produce 6,6-disubstituted-6,11-dihydro-5H-indolo[3,2-c]-
quinolones.
ation of 2-alkynylaniline has received special attention,[10]
because it provides direct access to C2-functionalized ind-
oles. Among various metal complexes, gold catalysts, owing
to their unique alkynophilicity, have engrossed a significant
role in facilitating cycloisomerization of a wide range of
alkynes tethered with different nucleophiles.[11] These gold
catalysts also act as Lewis acids for the activation of electro-
philes[12] to facilitate C–C and C–X bond formation.
Introduction
The design and synthesis of pharmaceutically relevant
heterocycles in a one-pot strategy is still a challenging task
for synthetic chemists. In particular, the spirooxindole motif
is a privileged pharmacophore and is found in numerous
naturally occurring alkaloids and pharmaceutically impor-
tant lead compounds (Figure 1).[1–3] A few of these com-
pounds have been reported as cell cycle regulators (spiro-
typrostatin A),[4] modulators of muscarinic M1 and 5-HT2
receptors (pteropodin),[5] and also as inhibitors of tubulin
polymerization (spirotryprostatin B).[6] Among them, spiro-
indolones represent an important class of spirocycles owing
to their promising antiplasmodial activity.[7] For instance,
NITD609 was found to display potent antimalarial activity
in a mouse model. Consequently, a large number of reports
related to the synthesis of spirooxindoles have been devel-
oped over the last decade.[8] In view of the biological impor-
tance of spirooxindoles, there is a need to develop simple
and more efficient synthetic protocols for their synthesis.
Many naturally occurring alkaloids and biologically active
molecules possess a 2-substituted indole motif as a core
structure,[9] and these derivatives have displayed a broad
spectrum of biological activities such as antiestrogen,[9b,9d]
5-HT2A antagonist,[9f] anti-inflammatory,[9a,9c] and cyto-
toxic behavior.[9e] Of various approaches, the hydroamin-
[a] Natural Products Chemistry Department, CSIR – Indian
Institute of Chemical Technology,
Figure 1. Spirooxindole-containing biologically active molecules.
Hyderabad 500007, India
E-mail: basireddy@iict.res.in
www.iictindia.org
Inspired by the unique catalytic properties of gold com-
plexes, we also reported a domino reaction for the synthesis
of tetrahydropyrido[4,3-b]indole scaffolds of pharmaceuti-
cal interest.[13] Following our interest in exploring novel
routes for the synthesis of biologically active heterocycles
[b] Laboratory of X-ray Crystallography, CSIR – Indian Institute
of Chemical Technology,
Hyderabad 500007, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402006.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. V. S. Reddy, M. Swain, S. M. Reddy, J. S. Yadav, B. Sridhar
SHORT COMMUNICATION
with high molecular complexity,[14] we herein report a novel nation with an AgI salt was efficient or the optimal catalyst
strategy for the one-pot synthesis of spiroindolones from 2- for this reaction, and product 3a was obtained in only mod-
[(2-aminophenyl)ethynyl]phenylamines and isatins through erate yield (Table 1, Entries 5 and 6). Similarly, a low yield
intramolecular hydroamination followed by Pictet–Spengler of product 3a was obtained if the reaction was performed
spirocyclization.
by using AuCl (10 mol-%) in DCE at 25 °C (Table 1, En-
tries 11 and 12). Indeed, an improved yield of 3a was
achieved by using NaAuCl4·2H2O (10 mol-%) in EtOH at
25 °C within 1.5 h (Table 1, Entry 8). To our delight, a sim-
ilar yield and selectivity were observed even by reducing the
catalyst loading to 5 mol-% in ethanol. However, the yield
of 3a slightly decreased to 81% if ethanol was replaced by
acetonitrile (Table 1, Entry 10). The reason may be attrib-
uted to the poor solubility of isatin. After screening several
gold catalysts, the best conversions were achieved by em-
ploying NaAuCl4·2H2O (5 mol-%) in ethanol at 25 °C, and
these conditions were chosen as the optimized conditions
(Table 1).
The scope of the reaction was further evaluated with re-
spect to various isatins. As shown in Table 2, a wide range
of mono- and disubstituted isatin derivatives participated
well in this reaction to generate the dihydrospiro[indoline-
3,6Ј-indolo[3,2-c]quinolin]-2-one derivatives, which are ana-
logues of the Novartis antimalarial lead compound
NITD609. Notably, several functional groups including hal-
ides, NO2, and OCF3 on the aromatic ring were well toler-
ated under the reaction conditions. Gratifyingly, N-pro-
tected isatin derivatives, including substrates with methyl,
allyl, and benzyl protecting groups, also gave the desired
products in fairly good yields (66–75%; Table 2, Entries 10–
12). In the case of 4,7-dichloroisatin, the product was ob-
tained in low yield after a long reaction time, which may be
due to steric hindrance of the 4,7-dichloro substituents
(53%, 6 h; Table 2, Entry 13). However, the electronic ef-
fects of the substituents on the aromatic ring did not show
any catalytic effect on the outcome of the reaction. Thus, a
series of dihydrospiroindolones were successfully synthe-
sized in good yields by using this protocol (Table 2).
Results and Discussion
Accordingly, we first attempted the coupling of 2-[(2-
aminophenyl)ethynyl]phenylamine (1) with isatin (2) in the
presence of IPrAuCl [10 mol-%, IPr = 1,3-bis(2,6-diiso-
propylphenyl)imidazol-2-ylidene] and AgSbF6 in 1,2-
dichloroethane (DCE) at 25 °C. Interestingly, spiroindolone
3a was isolated in 70% yield after 6 h (Table 1, Entry 6).
Inspired by these promising results, we began a systematic
screening of various Lewis acids such as Cu(OTf)2, In(OTf)
3, and AgOTf (Tf = trifluoromethylsulfonyl) to improve the
yield and reaction time. Only a trace amount of 3a was
obtained if the reaction was performed with Cu(OTf)2
(10 mol-%) in DCE, although Cu(OTf)2 is known to facili-
tate the intramolecular hydroamination of N-protected eth-
ynylaniline[15] (Table 1, Entry 1).
Table 1. Screening of various catalysts in the formation of 3a.[a]
Entry
Catalyst (mol-%)
Solvent
T
[°C]
Time Yield[b]
[h]
[%]
1
2
3
Cu(OTf)2
In(OTf)3 (10)
InCl3 (10)
DCE
DCE
DCE
DCE
DCE
25
25
25
25
25
25
25
25
25
24
16
7
6
12
8
trace
42[c]
60
4
5
AgOTf (10)
PPh3AuCl (10)
40
20[c]
70
6
7
8
9
10
11
12
PPh3AuCl + AgSbF6 (10) DCE
AuIPrCl + AgOTf (10)
NaAuCl4·2H2O (10)
NaAuCl4·2H2O (5)
NaAuCl4·2H2O (5)
AuCl (10)
DCE
EtOH
EtOH
CH3CN 25
DCE
DCE
6
68
85
85
81
55
80
1.5
1.5
1.5
20
12
25
80
AuCl (10)
[a] Reactions were performed with 1 (0.50 mmol, 1.1 equiv.) and 2a
(0.45 mmol, 1.0 equiv.) in dry solvent (2 mL). [b] Yield of isolated
product after column chromatography. [c] Both an intermediate
and isatin were recovered.
Similarly, other metal triflates such as In(OTf)3 and Ag-
OTf also afforded desired adduct 3a in low yields (42 and
40%, respectively; Table 1, Entries 2 and 4). A slight in-
crease in the yield was observed if the reaction was per-
formed by using InCl3 (10 mol-%) in DCE at room tem-
perature (Table 1, Entry 3). To know the catalytic efficacy
of various gold complexes, we next performed the reaction
by using PPh3AuCl, PPh3AuCl/AgOTf, NaAuCl4·2H2O,
and AuCl. To our surprise, neither Ph3PAuCl nor its combi- Figure 2. ORTEP diagram of 3b.
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Synthesis of Spiroindolone and Indolo[3,2-c]quinolone Scaffolds
Table 2. AuIII-catalyzed coupling of 2-[(2-aminophenyl)ethynyl]phenylamine[17] with isatins.[a]
[a] Unless otherwise noted, all reactions were performed by using NaAuCl4·2H2O (5 mol-%), 1 (1.1 equiv.), and isatin 2 (1.0 equiv.) in
dry ethanol at 25 °C. [b] Yield refers to pure products after column chromatography.
Eur. J. Org. Chem. 2014, 3313–3318
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B. V. S. Reddy, M. Swain, S. M. Reddy, J. S. Yadav, B. Sridhar
SHORT COMMUNICATION
The structure of 3b was confirmed by single-crystal X- as depicted in Table 4. Although, these catalysts failed to
ray diffraction analysis (Figure 2).[16]
promote the reaction at 25 °C (Table 4, Entries 1, 3–5), de-
To demonstrate the versatility of the reaction, we turned sired product 3a was formed in low yield at high tempera-
our efforts toward the cyclization of 1 with simple ketones. ture after a longer reaction time with HCl (10 mol-%) (1 m
Interestingly, the desired 6,6-disubstituted 6,11-dihydro-5H- in dioxane) and with TfOH (5 mol-%; Table 4, Entries 2
indolo[3,2-c]quinolones were obtained in good yields if acy- and 6). Further, to study the effect of the acid that was
clic ketones were used (45–70%; Table 3, Entries 1–3). Both formed in situ under the reaction conditions, a control ex-
acyclic and cyclic ketones successfully participated in the periment was performed by using K2CO3 (5 mol-%) along
reaction to furnish desired products 5 in moderate to good with NaAuCl4·2H2O (5 mol-%) in ethanol at 25 °C. To our
yields (Table 3).
delight, the reaction proceeded smoothly under the above
conditions to afford 3a in 85% yield in 1.5 h, as shown in
Scheme 1. These results clearly ruled out Brønsted acid ca-
talysis in the reaction.
Table 3. AuIII-catalyzed coupling of 2-[(2-aminophenyl)ethynyl]-
phenylamine with ketones.[a]
Table 4. Screening with Brønsted acids in the formation of 3a.[a]
Entry Catalyst (mol-%) Solvent
T
[°C]
Time Yield 3a[b]
[h]
[%]
1
2
3
4
5
6
HCl (10)
HCl (10)
HOAc (10)
PTSA·H2O (10)
TfOH (5)
CH3CN
CH3CN
EtOH
CH2Cl2
CH2Cl2
CH2Cl2
25
80
25
25
25
40
24
24
24
24
48
48
n.r.[c]
Ͻ50[d]
0
0[e]
trace
Ͻ20
TfOH (5)
[a] Reactions were performed with 1 (0.50 mmol, 1.1 equiv.) and 2a
(0.45 mmol, 1.0 equiv.) in dry solvent (2 mL). [b] Yield of isolated
product. [c] n.r. = no reaction. [d] Both starting material and isatin
were recovered. [e] Undesired products were obtained.
Scheme 1. Effect of base in the reaction.
A plausible mechanism is shown in Scheme 2. According
to the experimental observations, the reaction is assumed
to proceed by coordination of an AuIII species to the alkyne
moiety of 1 followed by nucleophilic attack of the tethered
amino group and subsequent protodemetalation to lead to
N-(2-aminophenyl)indole 1b. Thus-formed 1b may undergo
condensation with isatin, which is activated by AuIII to af-
ford imine 1c. Finally, activation of the imine by cationic
[a] Reactions were performed with 1 (0.5 mmol) and 2 (0.75 mmol)
in acetone (2 mL). [b] All the products were characterized by 1H
NMR, 13C NMR, and IR spectroscopy and HRMS. [c] Yield refers
to pure product after column chromatography.
To understand the reaction pathway and whether the re- gold species facilitates the nucleophilic attack of the indole
action was catalyzed by a Brønsted acid or gold(III), we onto imine 1c to afford 3. The proposed mechanism was
performed some control experiments by using various further verified by performing the individual reaction of 1b
Brønsted acids such as HCl, HOAc, p-toluenesulfonic acid with isatin, which also afforded 3a, the same as the one-pot
(PTSA·H2O), and TfOH under mild and harsh conditions, reaction.
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Eur. J. Org. Chem. 2014, 3313–3318

Synthesis of Spiroindolone and Indolo[3,2-c]quinolone Scaffolds
Experimental Section
Typical Procedure for the NaAuCl4·2H2O-Catalyzed Cyclisation:
NaAuCl4·2H2O (5 mol-%) was added to a stirred solution of 2-[(2-
aminophenyl)ethynyl]phenylamine[17]
(1)/N-[4-(2-amino-5-meth-
oxyphenyl)but-3-yn-1-yl]-4-methylbenzenesulfonamide (0.5 mmol)
and isatin 2/ketone 4 (0.45/0.75 mmol) in dry ethanol (2 mL) under
N2, and the resulting mixture was stirred at room temperature. The
progress of the reaction was determined by monitoring (TLC) the
disappearance of the starting material (Table 1). Removal of the
solvent followed by purification by silica gel column chromatog-
raphy (ethyl acetate/acetone, 4:1 to 1:1) afforded pure product 3/5.
Typical Procedure for the Formation of 2-(3-Iodo-1H-indol-2-yl)anil-
ine: NaAuCl4·2H2O (5 mol-%) was added to a stirred solution of
2-[(2-aminophenyl)ethynyl]phenylamine (1; 0.5 mmol) in ethanol
under N2 followed by N-iodosuccinimide (0.6 mmol), and the re-
sulting mixture was stirred at room temperature for 2 h. Removal
of the solvent followed by purification by silica gel column
chromatography (ethyl acetate/acetone, 9:1) afforded pure 2-(3-
iodo-1H-indol-2-yl)aniline as a brown semisolid.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures, spectroscopic data (1H and
13C NMR), crystallographic data.
Scheme 2. Plausible reaction pathway.
Evidence for the formation of the vinyl–AuIII species was
further confirmed by trapping it with N-iodosuccinimide
(NIS), which provided the corresponding 2-(3-iodo-1H-
indol-2-yl)aniline in 80% yield, as shown in Scheme 3.
Acknowledgments
M. S. and S. M. R thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, for the award of fellowships. B. V. S.
thanks the CSIR, New Delhi for financial support as part of the
XIIth five-year plan under the title DENOVA (CSC-0205).
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Conclusions
We successfully demonstrated a simple and efficient one-
pot strategy for the synthesis of 5Ј,11Ј-dihydrospiro-
[indoline-3,6Ј-indolo[3,2-c]quinolin]-2-one
through 5-endo-dig spirocyclization from readily accessible
starting materials. This tandem process exhibits significant
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B. V. S. Reddy, M. Swain, S. M. Reddy, J. S. Yadav, B. Sridhar
SHORT COMMUNICATION
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Received: February 3, 2014
Published Online: April 14, 2014
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