Cycloisomerization of Oxindole-Derived 1,5-Enynes: A Calcium(II)-Catalyzed One-Pot, Solvent-free Synthesis of Phenanthridinones, 3-(Cyclopentenylidene)indolin-2-ones and 3-Spirocyclic Indolin-2-ones

Article abstract of DOI:10.1002/adsc.201700569

Calcium-catalyzed regioselective synthesis of oxindole-derived 1,5-enynes, followed by cycloisomerization, from readily accessible 3-hydroxy-3-(alkynyl)indolin-2-ones and styrenes in one-pot, under solvent-free conditions is described. This method offers the synthesis of diverse molecules: phenanthridinones, 3-(cyclopentenylidene)indolin-2-ones, and 3-spirocyclic indolin-2-ones are obtained through cascade reactions including cross-dehydrative-coupling, [3,3]-sigmatropic rearrangement, carbocyclization, isomerization, oxidative-ring rearrangement, and Diels-Alder cycloaddition. In addition, this method features atom- and step-economy, broad substrate scope, and high yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201700569

Title: Cycloisomerization of Oxindole-derived 1,5-enynes: A Calcium(II)
catalyzed one-pot, solvent-free synthesis of Phenanthridinones,
3-(cyclopentenylidene)indolin-2-ones and 3-spirocyclic indolin-2-
ones
Authors: SRINIVASARAO YARAGORLA, Abhishek pareek, and
Ravikrishna Dada
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700569
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10.1002/adsc.201700569
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.2017((will be filled in by the editorial staff))
Cycloisomerization of Oxindole-Derived 1,5-Enynes: A
Calcium(II)-Catalyzed One-Pot, Solvent-free Synthesis of
Phenanthridinones, 3-(Cyclopentenylidene)indolin-2-ones and 3-
Spirocyclic Indolin-2-ones
Srinivasarao Yaragorla,a,b*Abhishek Pareeka,b and Ravikrishna Dadaa,b
aSchool of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Hyderabad, 500046, India.
Email:srinivas.yaragorla@uohyd.ac.in
bDepartment of Chemistry, Central University of Rajasthan, NH8, Bandersindri, 305817, Rajasthan, India
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######. (Please
delete if not appropriate)
handle the reaction. Furthermore, all these methods
by utilize the 1,5-enynes as precursor. To the best of our
knowledge, no report has been available for the in situ
Abstract. Calcium-catalyzed regioselective synthesis of
oxindole-derived 1,5-enynes, followed
cycloisomerization, from readily accessible 3-hydroxy-3-
(alkynyl)indolin-2-ones and styrenes in one-pot, under
solvent-free conditions is described. This method offers the
synthesis of diverse molecules: phenanthridinones, 3-
(cyclopentenylidene)indolin-2-ones, and 3-spirocyclic
indolin-2-ones are obtained through cascade reactions
including cross-dehydrative-coupling, [3,3]-sigmatropic
rearrangement, carbocyclization, isomerization, oxidative-
ring rearrangement, and Diels-Alder cycloaddition. In
addition, this method features atom- and step-economy,
broad substrate scope, and high yields.
generation
of
1,5-enynes
followed
by
cycloisomerization and also no non-transition metal
has been used for the enyne isomerization yet. Owing
to these reasons, it is certainly desirable to explore
highly abundant, environmentally benign and less
expensive catalysts for the facile synthesis and
transformation of 1,5-enynes in a one-pot cascade
strategy which can contribute to the sustainable goals
of organic synthesis.[8] In the past few years we have
been working with Ca(OTf)2 as one of the alternatives
and sustainable catalyst for varieties of tandem organic
transformation with high regioselectivity.[9] In
continuation of our research interest towards the
Keywords: 1,5-enynes; cycloisomerization; Diels-Alder
reaction; phenanthridinones; regioselective; calcium
catalysis
alkyne
triggered
regioselective
annulation
reactions,[10] we disclose here a calcium catalyzed
one-pot tandem process of 1,5-enyne formation and
their cycloisomerizations from the readily available -
methylstyrenes/benzylic-tert-alcohols and 3-hydroxy-
3-(alkynyl)indolin-2-ones.
Enynes are highly potential feedstock materials for
the synthesis of complex carbocyclic molecules,
natural products and pharmaceutically active
molecules through varieties of cycloisomerization
reactions.[1] The substantial increase in the
molecular/structural complexity arises from the simple
acyclic starting materials made this method more
significant.[1,2] In most of the cases transition metals
were employed for cycloisomerization and
rearrangement of enynes for developing useful organic
transformations and hence considerably great research
has
been
devoted
towards
the
cycloisomerization/rearrangement of 1,n-enynes using
Pd, Ru, Rh, Ir, Pt, Au, Hg, Ti, Cr, Fe, Co, Ni, Cu, Ag,
In and Ga metal catalysts.[2] Amongst the array of
available enynes, 1,5-enynes are one of the most
studied and they have been efficiently converted into
carbocyclic compounds such as bicycloalkenes,[3]
tricyclic compounds,[4] cyclohexadienes[5] and
methylenecyclopentenes.[6] Most of these metal
catalyzed transformations are inherently atom
economical,[7] however some of these catalysts are
expensive and need special conditions (mostly inert) to
Scheme 1. Our conceptualization of one-pot 1,5-enyne
formation and cycloisomerization cascade.
1
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10.1002/adsc.201700569
Advanced Synthesis & Catalysis
As depicted in the Scheme 1, we proposed that the 1,5-
enyne 3 can be synthesized through a dehydrative
cross coupling of alcohol 1 and olefin 2. 1,5-enyne 3
thus obtained further would undergo a thermal [3,3]-
sigmatropic rearrangement to furnish the allene
intermediate 3aa which has two possible modes of
intramolecular cyclization i.e. (i) a 5-exo/endo
cyclization to yield the cyclopentenylidene 4; (ii) 6-
endo cyclization to furnish the cyclohexadiene 3ab.
Diene 3ab could be trapped into a Diels-Alder
cycloaddition (6) or it can undergo oxidative
rearrangement to provide the phenanthridinones (5)
(phenylethynyl)indolin-2-one) as the sole product with
94% yield in 1.5 h (Table 1, entry 1). When the
reaction temperature raised to 110 C we found that
o
most of the 1,5-enyne underwent cycloisomerization
to form spirohexadiene (regioisomeric mixture) 3ab in
75% after 3 h. Further increase in temperature to 130
oC, spirocyclic hexadiene 3ab was rearranged to a
stable cyclopentene derivative 4a in 73% after 7 h
(entry 3). The absence of Ca(OTf)2/Bu4NPF6 (entry 4)
or presence of catalyst alone (entry 5) or additive
(Bu4NPF6) alone (entry 6) was found to be inefficient.
Neither the decrease of catalyst loading nor the change
in catalyst/additive combinations could give the
satisfactory results (Entries 7-11). Other calcium salts
such as CaCl2 and Ca(ClO4)2 were ineffective (entries
12, 13). Solvents such as toluene, water and
dichloromethane were not found to be suitable
solvents (entries 14-16). Other catalysts such as
Mg(OTf)2, p-TSA and FeCl3 could not give the
satisfactory results (entries 17-19).
Table 1. Optimization of reaction conditions for one-pot
regioselective
synthesis
of
3-(cyclopent-2-en-1-
ylidene)indolin-2-ones [a]
Entry
Catalyst (mol%)
Reaction
Conditions.b
Yields (%)
of
3a, 3abc,
4a
Ca(OTf)2/Bu4NPF6, (10/10)
1d
2
3e
neat, 80 oC, 1.5 h
neat, 110 oC, 3 h
neat, 130 oC, 7 h
94, 0, 0
10, 75, 0
0, 12, 73
----
Ca(OTf)2/Bu4NPF6, (10/10)
Ca(OTf)2/Bu4NPF6, (10/10)
neat, 130 oC, 24 h
4
--
neat, 130 oC, 12 h
5
Ca(OTf)2, (10)
12, 0, 0
10, 0, 0
0, 5, 60
0, 15, 60
0, 10, 65
0, 25, 0
0, 10, 0
0, 15, 0
neat, 130 oC, 12 h
neat, 130 oC, 8 h
6
Bu4NPF6, (10)
Ca(OTf)2/Bu4NPF6, (5/5)
7
Ca(OTf)2/Bu4NPF6, (5/10)
Ca(OTf)2/Bu4NPF6, (10/5)
Ca(OTf)2/KPF6, (10/10)
Ca(OTf)2/Bu4NF, (10/10)
CaCl2/Bu4NPF6, (10/10)
neat, 130 oC, 8 h
8
neat, 130 oC, 8 h
9
neat, 130 oC, 10 h
neat, 130 oC, 10 h
neat, 130 oC, 10 h
neat, 130 oC, 10 h
10
11
12
13
Ca(ClO4)2/Bu4NPF6,
(10/10)
Ca(OTf)2/Bu4NPF6, (10/10)
0, 10, 0
toluene, 120 oC, 10
h
water, 110 oC, 10 h
14
0, 40, 30
-
Ca(OTf)2/Bu4NPF6, (10/10)
Ca(OTf)2/Bu4NPF6, (10/10)
Mg(OTf)2/Bu4NPF6, (10/10)
15
16
17
18
19
Scheme 2. Synthesis of quaternary-oxindolyl 1,5-enynes
through calcium triflate mediated a dehydrative cross
coupling. General conditions:1 equiv. of 1a, 2.2 equiv. of
2a, 10 mol% of Ca(OTf)2, 10 mol% of Bu4NPF6. Isolated
yields.
DCM, 50 oC, 10 h
45, 0, 0
0, 20, 30
neat, 130 oC, 8 h
neat, 130 oC, 8 h
neat, 130 oC, 8 h
p-TSA (10)
FeCl3 (10)
0, 10, 40
0, 25, 40
aConditions: 1 equiv. of 1a and 2.2 equiv. of 2a were used. bOil bath temperature.
cRegioisomeric hexadiene (1:0.35). dOptimum condition for the 1,5-enynes.
eOptimum condition for the cyclopentenylidene; DCM = dichloromethane; Tf=
trifluormethanesulfonyl; p-TSA = para toluene sulfonic acid.
Considering the entry 1 (Table 1) as the standard
condition for the synthesis of quaternary-oxindolyl
1,5-enynes, we extended this protocol to check its
substrate scope. As depicted in the Scheme 2, we
synthesized the 1,5-enynes with the substitution on
isatin-aryl ring 3b, 3c in 91% and 92% respective
yields. Not only aryl alkynes but also aliphatic alkynes
gave 1,5-enynes 3d, 3e and 3f in excellent yields as
depicted in the Scheme 2. Substituted -
methylstyrenes such as 1-chloro-4-(prop-1-en-2-
yl)benzene and 1-methoxy-4-(prop-1-en-2-yl)benzene
also showed good reactivity towards the enyne
formation, however owing to the +M-effect of _-OMe
Based on our preliminary results from the synthesis of
internal olefins through
a
calcium catalyzed
dehydrative cross coupling of alcohols with olefins,[9a]
we chose 3-hydroxy-3-(phenylethynyl)indolin-2-one
(1a) and -methylstyrene (2a) as the substrates for the
synthesis of 1,5-enyne 3a and hence heated them at 80
oC with 10 mol% of Ca(OTf)2/Bu4NPF6. Gratifyingly,
this reaction proceeded with high efficiency to furnish
the
1,5-enyne
3a
(3-(2-phenylallyl)-3-
2
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10.1002/adsc.201700569
Advanced Synthesis & Catalysis
group the yield of 3h (1.5 h, 87%) is slightly higher
than that of 3g (2.5 h, 81%), Table 1.
this strategy (Table 3). The substitutions on the isatin
aryl ring (1a) with 5-chloro, 5-flouro, 5-methyl, 7-
fluoro were equally tolerated by this protocol and
yielded the respective phenanthridinones 5b, 5c, 5d
and 5e in good yields. N-methyl isatin derivative 1n
gave 74% of 5f. Another styryl derivative 1-methyl-4-
(prop-1-en-2-yl)benzene also showed good reactivity
in the one-pot, tandem dehydrative cross-
coupling/cycloisomerization/thermal-oxidative ring
rearrangement to furnish the phenanthridinones 5g, 5h
and 5i in moderate to good yields. Thus this protocol
would be the superior to all the existing methods for
the synthesis of phenanthridinones due to its simple
operation conditions, easily available starting
materials, one-pot and tandem process with atom and
step economy.
Encouraged by this result, we decided to check the
scope of the Ca(II) catalyzed tandem 1,5-enyne
formation and its cycloisomerization to synthesize
structurally diversified cyclopentenylidenes as showed
in the Table 2. Thus, alkynol derivatives 1b (5-fluoro),
1c (5-chloro) and 1d (5-methyl) were heated
independently with styrene 2a under standard
conditions
to
furnish
the
respective
cyclopentenylidenes 4b, 4c and 4d in good yields. 3-
hydroxy-3-(p-tolylethynyl)indolin-2-one derivatives
1e, 1f and 1g also furnished respective cp-derivatives
4e, 4f and 4g in good yields as shown in the Table 2.
Interestingly, when -methyl styrene 2a was replaced
with 2-(p-tolyl)propan-2-ol (2b) and treated with
alkynol (1) the reaction proceeded with the same ease
and yielded the respective products 4h, 4i and 4j. Here
the tertiary alcohol (2b) has undergone a calcium (II)
catalyzed E1 elimination to furnish the styryl
derivative, which further took part in the dehydrative
cross coupling. N-alkyl derivatives of 1, such as 1h, 1i
and 1j reacted with 2a to furnish 4k, 4l and 4m in very
good yields (Table 2, second row). The scope of
aliphatic alkynols (1k, 1l and 1m) was also
successfully demonstrated by synthesizing the cp-
derivatives 4n, 4o and 4p in good yields. Interestingly,
when 3-hydroxy-1-methyl-3-(phenylethynyl)indolin-
2-one (1n) was treated with 2a under standard
conditions, we observed that after the formation of
cyclopentenylidene, a Friedel-Crafts type reaction
took place on the 5-position of oxindole with the
excess styrene to yield 4q in 63% after 10 h. This
domino approach was further reproduced with alkynol
1o while synthesizing 4r in 66% yield. -
methylstyrene bearing electron acceptor group such as
1-chloro-4-(prop-1-en-2-yl)benzene gave 63% of 4s in
6.5 h.
Table
2.
One-pot
1,5-enyne
synthesis
and
cycloisomerization to furnish 3-(cyclopent-2-en-1-
ylidene)indolin-2-ones via a Ca(II) catalysis.[a]
It was observed that the cycloisomerization of 1,5-
enyne (3) proceeded through a spirocyclic hexadiene
intermediate (3ab) to furnish cyclopentenylidene 4.
Since 3ab is thermally unstable it has undergone a
rearrangement to furnish the cyclopentenylidene 4.
Taking the advantage of thermal instability of 3ab, we
anticipated that the spirocyclic compound 3ab can also
undergo a thermal-oxidative- ring rearrangement to
furnish phenanthridinone 5. Phenanthridinone is a key
structural motif present in many of the biologically
active natural alkaloids and pharmaceuticals with a
broad range of activities such as antitumor, antivirus
and as DNA topoisomerase inhibitor.[11] Owing to
these reasons, the synthesis of this motif has been
intensively pursued during the past decade.[12] In order
to implement our idea, 1a and 2a were heated at 110
oC with 10 mol% of Ca(OTf)2/Bu4NPF6 for 2 h and
then chloranil was added to the reaction mixture at 150
oC.[13] After continuing the reaction for 4.5 h, we were
glad to isolate the 7,9-diphenylphenanthridin-6(5H)-
one 5a in 72% yield (Table 3).[14] Encouraged by this
results, we also demonstrated the substrate scope of
aGeneral conditions:1 equiv. of 1a, 2.2 equiv. of 2a, 10
mol% of Ca(OTf)2, 10 mol% of Bu4NPF6. Isolated yields.
3
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10.1002/adsc.201700569
Advanced Synthesis & Catalysis
Encouraged by the successful utilization of
spirocyclic-hexadiene 3ab for the synthesis of
phenanthridinone (Table 3), strategically we planned
to trap this diene intermediate 3ab into a thermal [4+2]
cycloaddition reaction (Diels-Alder)[15] and to study
the stereoselectivity of the adduct. In order to execute
the concept, 1a and 2a were heated at 110 oC with 10
mol% of Ca(OTf)2/Bu4NPF6 for 2 h (formation of
diene 3ab was observed by TLC) then maleic
anhydride (enophile) was added to the reaction and
The detailed mechanism for this tandem process
has been delineated in the Scheme 3. Initially, a
calcium(II) mediated dehydrative cross coupling
reaction takes place between propargyl alcohol
and -methylstyrene to furnish the 1,5-enyne
Then the enyne would undergo a thermal [3,3]-
sigmatropic rearrangement at 130 C and furnish
the allene intermediate 3aa [17]
which could
immediately cycloisomerizes to the trisubstituted
cyclopentenylidene 4 [18]
3aa can also undergo
exocyclization to furnish the spirohexadiene 3ab
which can further rearrange to stable
cyclopentenylidene . In presence of enophile
1
3.

2
3
o
,
o
.
then the temperature was raised to 150 C. To our
delight and as proposed we were able to isolate the exo
adduct 6a as the single diastereomer in 67%.[16] The
scope of substituted isatin derivatives (1) was
demonstrated in this cascade reaction by using 5-
chloro, N-methyl, N-allyl, N-benzyl and 5-chloro-N-
benzyl derivatives to furnish the single exo isomers 6b,
6c, 6d, 6e and 6f in good yields as described in the
Table 4. The scope of styryl derivatives has also been
demonstrated by synthesizing the Diels-Alder adducts
6g, 6h, 6i, 6j, 6k and 6l in moderate to good yields
(Table 4).
a
4
such as maleic anhydride, spirocyclohexadiene
3ab can be trapped into a [4+2] cycloaddition
(Diels-Alder) reaction to furnish the DA-adduct 6.
When treated with oxidative agents such as
chloranil, 3ab underwent oxidative ring
rearrangement (benzannulation) to furnish the
phenanthridinone 5.
Table 4. Ca(II)-catalyzed one-pot, regioselective
dehydrative cross-coupling/cycloisomerization/Diels-
Alder cascade.[a]
Table 3. Synthesis of phenanthridinones through a
cascade 1,5-enyne formation/ cycloisomerization/
oxidative ring-rearrangement.[a]
aGeneral conditions:1 equiv. of 1a, 2.2 equiv. of 2a, 10
aGeneral conditions:1 equiv. of 1a, 2.2 equiv. of 2a, 10
mol% of Ca(OTf)2, 10 mol% of Bu4NPF6. After 2 h at
110 oC chloranil (2.2 equiv) was added and the
mol% of Ca(OTf)2, 10 mol% of Bu4NPF6. After 2 h at
o
110 C maleic anhydride (2.2 equiv) was added and
temperature raised to 150 oC. Isolated yields. bstructure
confirmed by X-ray analysis.
temperature raised to 150 oC. Isolated yields
.
4
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10.1002/adsc.201700569
Advanced Synthesis & Catalysis
A mixture of propargyl alcohol 1a (100 mg, 0.4 mmol), -
methyl styrene 2a (104.2 mg, 0.88 mmol) along with
Ca(OTf)2 (13.6 mg, 0.04 mmol), Bu4NPF6 (15.6 mg, 0.04
In summary, we have developed a Ca(II)-
catalyzed highly regioselective, atom & step
economical, one-pot cascade strategy for the
oxindole-derived 1,5-enyne synthesis and their
o
mmol) were heated in 10 ml round bottom flask at 110 C
for 2 h, then chloranil (243.9 mg, 1 mmol) was added and
o
cycloisomerization
trisubstituted
reactions
to
furnish
the reaction was further heated at 150 C for 4-5 h. The
cyclopentenylidenes,
progress of reaction was monitored by TLC. After
completion of the reaction, the resulting mixture was diluted
with water and extracted with ethyl acetate (thrice).
Combined organic layers were washed with brine solution
and dried over anhydrous Na2SO4 and the solvent was
evaporated to get the crude product. The crude product was
purified by silica gel column chromatography to furnish the
pure product 5a in 72% (100.3 mg) yield.
benzannulation to yield phenanthridinones and
Diels-Alder cycloadditions to furnish the
stereoselective
3-spirocyclic
indolin-2-one
derivatives. For the first time, we have expanded
the scope of oxindole-derived 1,5-enyne
isomerization to furnish new chemical entities
which may be useful in organic, medicinal and
materials chemistry.
General procedure for the synthesis of Diels-Alder
adduct (6):
A mixture of propargyl alcohol 1a (100 mg, 0.4 mmol), -
methyl styrene 2a (104.2 mg, 0.88 mmol) along with
Ca(OTf)2 (13.6 mg, 0.04 mmol), Bu4NPF6 (15.6 mg, 0.04
mmol) was heated at the 110 oC for 2 h then maleic
anhydride (98.0 mg, 1 mmol) added further heated in 10 ml
o
round bottom flask at 150 C for 4-5 h. The progress of
reaction was monitored by TLC. After completion of the
reaction, the resulting mixture was diluted with water and
extracted with ethyl acetate (thrice). Combined organic
layers were washed with brine solution and dried over
anhydrous Na2SO4 and the solvent was evaporated to get the
crude product. The crude product was purified by silica gel
column chromatography to furnish the pure product 6a in
67% (120.2 mg) yield.
Supporting Information
Detailed descriptions of experimental procedures and their
spectroscopic data as well as the crystal structures are
presented in the Supporting Information. CCDC 1536897
(4k), 1527665 (5a) and CCDC 1536795 (6e) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Scheme 3. Plausible mechanism for the Ca(II)
catalyzed synthesis of 1,5-enynes and their
cycloisomerization
Experimental Section
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
General procedure for the synthesis of 3-
(cyclopentenylidene)indolin-2-ones (4):
Acknowledgements
A mixture of propargyl alcohol 1a (100 mg, 0.4 mmol), -
methyl styrene 2 (104.2 mg, 0.88 mmol) along with
Ca(OTf)2 (13.6 mg, 0.04 mmol), Bu4NPF6 (15.6 mg, 0.04
mmol) were heated in 10 mL round bottom flask at 130 oC
for 8-10 h. The progress of the reaction was monitored by
TLC. After completion of the reaction, the resulting mixture
was diluted with water and extracted with ethyl acetate
(thrice). Combined organic layers were washed with brine
solution and dried over anhydrous Na2SO4 and the solvent
was evaporated to get the crude product. The crude product
was purified by silica gel column chromatography to furnish
the pure product 4a in 73% (101 mg) yield.
This work is partially supported by SERB (SB/FT/CS-149/2012)
and CSIR (02/200/14/EMR-II) India. AP and RD thank Central
University of Rajasthan for the fellowships. Authors are grateful
to Dr. Gopal K and Mr. Sudhir M for the technical support in
solving the crystal structures.
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for
the
synthesis
of
phenanthridinones (5):
5
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10.1002/adsc.201700569
Advanced Synthesis & Catalysis
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6
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10.1002/adsc.201700569
Advanced Synthesis & Catalysis
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7
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10.1002/adsc.201700569
Advanced Synthesis & Catalysis
COMMUNICATION
Cycloisomerization of Oxindole-derived 1,5-
enynes: A Calcium(II) catalyzed one-pot, solvent-
free
synthesis
of
Phenanthridinones,
3-
3-
(cyclopentenylidene)indolin-2-ones
spirocyclic indolin-2-ones
and
Adv. Synth. Catal. Year, Volume, Page – Page
Srinivasarao Yaragorla,*a,b Abhishek Pareeka,b and
Ravikrishna Dadaa,b
8
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