Pd/C-mediated arylation followed by I2-catalyzed hydration strategy: Preparation of functionalized novel indanone derivatives

Article abstract of DOI:10.1080/00397911.2013.860554

A simple and inexpensive synthesis of novel 2-(3-oxo-3-arylpropyl)-2,3- dihydro-1H-inden-1-one derivatives has been achieved via Pd/C-mediated arylation followed by I₂-mediated regioselective hydration of 2-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-ones. A wide variety of 3-aryl substituted 2-propynyl indanone derivatives were conveniently prepared by using 10% Pd/C-PPh₃-CuI as a catalyst system, some of which were used to prepare the corresponding ketones via alkyne hydration in the presence of catalytic I₂. In an in vitro study a representative compound showed inhibition of PDE4B (phosphodiesterase type 4B) and binding with this protein in silico

Full text of DOI:10.1080/00397911.2013.860554

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PD/C-Mediated Arylation Followed by I2-catalyzed
Hydration Strategy: Preparation of Functionalized
Novel Indanone Derivatives
Balakrishna Dulla a b , Sunder Kumar Kolli c , Upendar Reddy CH a , Giridhar Singh Deora d ,
R. Ramesh Raju c & Manojit Pal a
a Department of Medicinal Chemistry, Dr. Reddy's Institute of Life Sciences , University of
HyderabadCampus , Hyderabad , 500046 , India
b InstitutfürOrganischeChemie , Universität Regensburg , Universitäts str. 31 , 93053 ,
Regensburg , Germany
c Department of Chemistry , AcharyaNagarjuna University , Guntur , 522510 , Andhra
Pradesh , India
d School of Pharmacy , \The University of Queensland , Brisbane , QLD , 4072 , Australia
Accepted author version posted online: 10 Feb 2014.Published online: 10 Feb 2014.
To cite this article: Synthetic Communications (2014): PD/C-Mediated Arylation Followed by I2-catalyzed Hydration Strategy:
Preparation of Functionalized Novel Indanone Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2013.860554
To link to this article: http://dx.doi.org/10.1080/00397911.2013.860554
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Manojit Pal., etal.,
Preparation of functionalized novel indanones
PD/C-MEDIATED ARYLATION FOLLOWED BY I2-CATALYZED
HYDRATION STRATEGY: PREPARATION OF FUNCTIONALIZED NOVEL
INDANONE DERIVATIVES
Balakrishna Dulla1,2, Sunder Kumar Kolli3, Upendar Reddy CH1, Giridhar Singh Deora4,
R. Ramesh Raju3, Manojit Pal1,
1Department of Medicinal Chemistry, Dr. Reddy’s Institute of Life Sciences, University of
HyderabadCampus, Hyderabad 500046, India2InstitutfürOrganischeChemie, Universität
Regensburg, Universitäts str. 31, 93053 Regensburg, Germany3Department of Chemistry,
AcharyaNagarjuna University, Guntur 522510, Andhra Pradesh, India.4The University of
Queensland, School of Pharmacy, Brisbane, QLD 4072, Australia
Address of correspondence to Manojit Pal: Institute of Life Sciences, University of
Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra Pradesh, India. E-
mail:manojitpal@rediffmail.com; Tel.:+91 40 6657 1500; fax: +91 40 6657 1581;
Abstract
A simple and inexpensive synthesis of novel 2-(3-oxo-3-arylpropyl)-2,3-dihydro-1H-
inden-1-one derivatives has been achieved via Pd/C-mediated arylation followed by I2-
mediated regioselectivehydration of 2-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-ones. A
wide variety of 3-aryl substituted 2-propynyl indanone derivatives were conveniently
prepared by using 10% Pd/C-PPh3-CuI as a catalyst system some of which were used to
prepare the corresponding ketones via alkyne hydration in the presence of catalytic I2. In
an in vitro study a representative compound showed inhibition of PDE4B
(phosphodiesterase type 4B) and binding with this protein in silico.
KEYWORDS: Indanone, alkyne, Pd/C, iodine, hydration
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INTRODUCTION
The development of newer and effective strategies for the quicker access to novel
compounds of potential pharmacological interest is of great value both in academic and
industrial R&Ds. Accordingly, we devoted our efforts towards the development of a
new strategy based on Pd/C-mediated arylation followed by I2-catalyzed
hydrationleading tofunctionalizedindanonederivatives.
Indanone derivatives represent an important class of pharmacologically active
molecules.[1-7] For example, indanocine (A, Fig. 1), a potent cytostatic and cytotoxic
indanoneinhhibits tubulin polymerization and induces apoptotic cell death in stationary-
phase multidrug-resistant cancer cells.[1] Similarly, another indanone analogue e.g.
donepezil hydrochloride (B, Fig. 1) that acts as AChE (Acetylcholinesterase) inhibitor
has been used for the treatment of Alzheimer’s disease.[2]Notably, both the molecule A
and B contain a 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one ring with which a side chain
is attached at C-2. These observations prompted us to design and synthesizeindanone
based library of novel small molecules represented by C (Fig. 1) in which the 5,6-
dimethoxy-2,3-dihydro-1H-inden-1-one ring was retained and new side chains were
added at C-2. Because of structural similarity of C with A and B we anticipated that
molecules based on C might show biological activities.
While a number of elegant approaches have been reported for the introduction of a
substituent at C-2 of the 5,6-dialkoxy-2,3-dihydro-1H-inden-1-one ring[3-8]none of them
however was applicable for the preparation of our target molecules C. We therefore
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required a new, straightforward and practical approach for this purpose and our major
focus was to develop a simple and inexpensive methodology. The strategy we adopted for
the synthesis of molecules based on C involved (i) an initial introduction of an alkynyl
moiety at C-2 of the indanone ring followed by (ii) its functionalization viaPd-mediated
reactions and then (iii) hydration of the triple bond. The Pd-catalyzed coupling of
terminal alkynes with the (hetero)aryl halide i.e. the Sonogashira coupling)[9,10]was the
methodology of our choice for this purpose. While a variety of Pd-catalysts [e.g.
Pd(PPh3)4, (PPh3)2PdCl2, Pd(OAc)2/PPh3 etc.]have been explored for the Sonogashira
reactions earlier, the use of Pd/C–CuI–PPh3 as a less expensive catalyst was found to be
attractive in recent time.[11]Due to our continuing interest in Pd/C-mediated alkynylation
of aryl and heteroaryl halides we decided to explore the Pd/C based methodology as a
key step for the synthesis of our target compounds. While the hydration of alkynes
leading to various carbonyl derivatives has been studied extensively for over more than
100 years the acid-free alkyne hydration has not been explored until recently. Thus, gold-
NHC (N-heterocyclic carbene) complex / silver hexafluoroantimonate catalyzed
hydration of various alkynes has been reported by Nolanet. al. in 2009.[12]Though several
other excellent methodologies have been reported for alkyne hydration[13-16] most of them
involved the use of expensive metal catalysts and/or complex ligands. Very recently, we
have observed that the use elemental iodine can be effective for the hydration of 2-
propynyl indanone derivatives in the absence of any additional acid catalysts or ligands.
Herein we report our preliminary results on Pd/C-mediated arylation followed by I2-
mediated hydration of 2-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-one derivatives (3and 4)
as shown in Scheme 1. To the best of our knowledge the use of sucha strategy based on
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Pd/C-mediated coupling followed by I2-catalyzed hydration[17]is not common in the
literature.
RESULTS AND DISCUSSION
The key starting material i.e. 2-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-ones (3 and 4)
were synthesized according to a procedure shown in Scheme 2. Thus, 5,6-dimethoxy-2,3-
dihydro-1H-inden-1-one (1) was converted to ethyl-5,6-dimethoxy-1-oxo-2,3-dihydro-
1H-indene-2-carboxylate (2) which was propargylated to give the alkyne 3. The ester
hydrolysis followed by decarboxylation of 2 afforded the other alkyne 4. Both the
alkynes i.e. 3 and 4 were then used for the coupling with a range of iodoarenes in the
presence of 10% Pd/C, PPh3, CuI and triethylamine in EtOH (Table 1). The reactions
proceeded well irrespective of the presence of electron donating (e.g. Me, MeO, Cl,
NH2etc) and electron withdrawing (e.g. NO2 or F) group on the iodoarene ringaffording
the desired internal alkynes 5 and 6via a C-C bond forming reaction. The reaction was
also successful when 5-iodoindoline-2,3-dione (entry 11 and 22, Table 1) and ethyl-2-
iodo-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate (entry 14, Table 1) were
employed as iodoarenes. Altogether, 22 new alkynes were prepared by using this
methodology in good yields except two cases (entry 9 and 20, Table 1) where the
corresponding1,4-dialkynyl benzene derivative was isolated as a side product. Indeed, an
increase in reaction time afforded theses side products i.e. 5l and 6l as major products
(Scheme 3).
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Having prepared a variety of 3-aryl substituted 2-propynyl indanone derivatives (5 and 6)
we then performed the I2-mediated hydration of some of these internal alkynes. These
reactions were carried out by using alkynes 5 or 6 (0.15 mmol), catalytic amount of
iodine (0.015mmol) in dichloromethane-H2O (4.9 mL of DCM +0.1 mL of H2O) at rt for
24h and results are summarized in Table 2. Several 2-(3-oxo-3-arylpropyl)-2,3-dihydro-
1H-inden-1-one derivatives (7 and 8) were prepared with high regioselectivityby using
this method in good yields. The formation of other regioisomersi.e. 2-(2-oxo-3-
arylpropyl)-2,3-dihydro-1H-inden-1-one derivatives was not observed in any of these
cases. Notably, the reaction did not proceed in the absence of I2 or when performed in dry
DCM indicating the key role played by both catalyst and water.
A plausible reaction mechanismfor the I2-mediated regioselectivehydration of 3-aryl
substituted 2-propynyl indanone derivatives (5 and 6) is shown in Scheme 4. The reaction
seems to proceed via activation of the triple bond by coordination to I+obtained from the
molecular iodine. This triggers a nucleophilicattack by the proximal carbonyl group onto
the activated triple bond to generate a cyclized vinyl iodide intermediateE-1 or E-2.
However the isolation of product 7 or 8suggests that the reaction followed a 6-endo-dig
process leading to the intermediate E-2. While the generation of E-1via a 5-exo-dig
process is allowed according to Baldwin’s rules[18]the intermediate E-1 however would
afford the corresponding regioisomers[i.e. 2-(2-oxo-3-arylpropyl)-2,3-dihydro-1H-inden-
1-one derivatives instead of the product 7 or 8]that were not isolated. The5-exo-dig
process thus appeared to be a less favored one in the present case perhaps due to the non-
favorable geometry associated with the 5-5 ring formation rather than the 5-6 ring.
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Nevertheless, arguably being the predominating intermediate the vinyl iodide species E-
2undergoes ring opening upon interaction with water to give the intermediate E-3(via
proto-deiodination) which finally undergoes isomerization to give the keto compound 7
or 8. Notably, though the participation of the ester moiety[16]of 5 in its regioselective
alkyne hydration cannot be ruled out completely the successful hydration of 6 that does
not possessan ester group suggests preferential participation of keto group over the ester.
We then assessed the potential biological activities of all these compounds i.e. 5-8
synthesized. Due to our longstanding interest in the identification of novel PDE4/TNF-
inhibitors[19-22]all these compoundswere tested for their PDE4 inhibitory properties
invitro using PDE4B enzyme assay.[23]Since the PDE4B subtype among the four subtypes
of PDE4 (e.g. A, B, C and D)has been indicated to have key role in inflammatory cell
regulation[24] hence inhibition of the PDE4B was thought to be beneficial for the potential
treatment of diseases like COPD and asthma without causing adverse effects.[25]Among
all the compounds tested, 5a showed >30% inhibition of PDE4B when tested at 30 µM
using a known inhibitor rolipram[26]as a reference compound. To understand its preferred
binding modes with the PDE4B protein, molecular modeling studies were performed
using co-crystal structural coordinates of PDE4B from the protein data. Since 5a can
exists in two optical isomers e.g.(R)- and (S)- hence both forms were used for the docking
studies. Based on docking results, no significant binding variations were observed
between (R)- and (S)- forms of 5a. The C-5 methoxy group of 5a was found to interact
with the His-278 residue of PDE4B protein via anH-bond (Fig. 2). The overall interaction
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of 5awith the PDE4B proteinwas indicated by the glide score obtained for 5a (-5.93 for R
and -5.48 for S-isomer;see supporting information, Table S-1).
CONCLUSIONS
In conclusion, we have disclosed a new, simple and inexpensive strategy for the synthesis
of novel indanonederivatives of potential pharmacological interest. These compounds
were prepared first time via(i) an initial introduction of an alkynyl moiety at C-2 of the
indanone ring followed by (ii) its arylationviaPd/C-mediated reactions and then (iii) I2-
mediated hydration of the triple bond. A wide variety of 3-aryl substituted 2-propynyl
indanone derivatives were conveniently prepared by using 10% Pd/C-PPh3-CuI as a
catalyst system in the presence of triethylamine in EtOH. Some of them were converted
to the corresponding ketones in the presence of I2without using any additional acid
catalysts or ligands. A representative compound 5a showed inhibition of PDE4B when
tested in vitro. Docking studies indicated that one of the methoxy groups of this molecule
played key roles in the interactions with the PDE4B protein. Overall, the synthetic
methodology presented here could be useful in constructing library of molecules related
to indanonehaving potential medicinal value.
EXPERIMENTAL
General Procedure for the Pd/C-mediated coupling of 2-(prop-2-ynyl)-2,3-dihydro-
1H-inden-1-ones (3 and 4) with iodoarenes:A mixture of iodo compound
(0.33mmol),10% Pd/C (0.0022mmol), PPh3 (0.0086mmol),CuI (0.022mmol) and
triethylamine (0.54mmol) in EtOH (5 mL) was stirred for 30 min undera nitrogen
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atmosphere. To this mixture was added alkyne3 or 4(0.33mmol) slowlyand the mixture
was refluxed and reaction was monitored by TLC. The mixturewas then cooled to room
temperature and filtered throughcelite; EtOH was removed under reduced pressure. The
residue was diluted with water (50 mL) and extracted with EtOAc (3 x 25 mL). The
organic layerswere collected, combined, washed with water (2 x 25 mL),dried over
anhydrous Na2SO4, filtered and concentrated. Theresidue thus obtained was purified by
column chromatographyusing to afford the titlecompounds.
Synthesis of ketones 7 and 8 via I2-mediated hydration of alkynes 5 and 6: To a
solution of alkyne 5 or 6 (0.15 mmol) dissolved in DCM-H2O (4.9 mL of DCM + 0.1 mL
of H2O) was added catalytic amount of iodine (0.015 mmol) and the mixture was stirred
at rt. After completion of the reaction (monitored by TLC) the mixturewas then diluted
with dichloromethane (25 mL) and washed with saturatedaqueoussolution of Na2S2O3(25
mL).The organic layer was dried over anhydrous Na2SO4, filteredand concentrated under
reduced pressure. The crude product obtained was purified by column chromatography.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website. the
publisher’s website will be a live link
ACKNOWLEDGEMENTS
The authors thank Dr. Kishore and his team for PDE4 assay and the management of
DRILS for support.
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Table 1. Pd/C-mediated coupling of 2-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-ones(3 and
4) with iodoarenes.a
MeO
MeO
MeO
MeO
Ar
10% Pd/C, PPh3, CuI
Et3N, EtOH, reflux
+
ArI
Z
Z
O
O
3
. Z = CO2Et
4. Z = H
5. Z = CO2Et
6. Z = H
Entry
Alkynes
ArI; Ar =
Time
(h)
2
Products (5 Yield (%) b
or 6)
(3 or 4)
1
3
3
3
3
3
3
3
3
3
3
3
Ph
5a
5b
5c
5d
5e
5f
63
75
63
92
89
87
87
92
34c
66
82
2
o-MeC6H4
m-MeC6H4
o-MeOC6H4
p-MeOC6H4
o-NO2C6H4
m-NO2C6H4
m-FC6H4
p-IC6H4
3
3
3
4
3
5
3
6
1.5
1.5
1
7
5g
5h
5i
8
9
2
10
11
m,p-di-ClC6H3
O
2
5j
5
5k
O
N
H
12
13
4
4
Ph
24
24
6a
6b
76
58
o-MeC6H4
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S
14
4
36
6c
87
EtO2C
15
16
17
18
19
20
21
22
4
4
4
4
4
4
4
4
o-MeOC6H4
p-MeOC6H4
o-NO2C6H4
m-NO2C6H4
m-FC6H4
24
24
16
16
12
12
2
6d
6e
6f
73
68
73
78
72
23c
70
65
6g
6h
6i
p-IC6H4
o-NH2(m-CH3)C6H3
6j
O
O
5
6k
N
H
aAll the reactions were performed using an appropriate iodoarene(0.33mmol),10% Pd/C
(0.0022mmol), PPh3 (0.0086mmol),CuI (0.022mmol), alkyne 3 or 4(0.33mmol) and
Et3N (0.54mmol) in EtOH (5 mL) at refluxing temperature undernitrogen.
bIsolated yields.
cCorresponding1,4-dialkynyl benzene derivative was isolated as a side product in this
case.
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Table 2. Synthesis of ketones 7and 8 viaI2-mediated hydration of alkynes 5and 6.a
O
MeO
MeO
MeO
I2
Ar
Ar
Z
CH2Cl2
H2O
rt, 24h
Z
MeO
O
O
7. Z = CO Et
8. Z = H
2
5. Z = CO2Et
6. Z = H
Entry
Alkynes (5 and Product (7 Yield (%)b
6)
and 8)
7a
1
2
3
4
5
6
5a
5b
5h
6a
6b
6h
87
85
63
84
82
65
7b
7c
8a
8b
8c
aAllreactions were carried out by using alkyne 5 or 6 (0.15 mmol), catalytic amount of
iodine (0.015 mmol) in DCM-H2O (4.9 mL of DCM + 0.1 mL of H2O) at rt for 24h.
bIsolated Yields
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Fig. 1. Example of known bioactive molecules (A and B) and novel small molecules C
based on indanoneframework.
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Fig. 2. Binding mode andinteractions of 5a (R and S)at the inhibitor binding site of
PDE4B.
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Scheme 1. Synthesis of 2-(3-oxo-3-arylpropyl)-2,3-dihydro-1H-inden-1-ones (7 and 8)
viaPd/C-mediated coupling followed by I2-mediated hydration strategy. Reagents and
conditions: (a) 10% Pd/C, PPh3, CuI, Et3N, EtOH, reflux, 1.5-24 h. (b) I2, CH2Cl2-H2O,
rt, 24h.
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Scheme 2. Synthesis of 2-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-ones(3 and 4). Reagents
and conditions: (a) Diethyl carbonate, NaH, toluene, reflux, 2h, yield 85%; (b) Propargyl
bromide, K2CO3, dry acetone, rt, 12h, yield 90%; (c) 30% NaOH, THF, reflux, 12h, yield
80%.
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Scheme 4. Proposed reaction mechanismfor the I2-mediated hydration of 3-aryl
substituted 2-propynyl indanone derivatives (5 and 6).
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