Synthesis of Functionalized Alkylidene Indanes and Indanones through Tandem Phosphine-Palladium Catalysis

Article abstract of DOI:10.1021/acs.orglett.5b00554

Densely functionalized alkylidene indanes and indanones can be prepared efficiently in one pot, in high yields with good stereoselectivities (in some cases exclusively the Z-isomer), through a route involving phosphine-catalyzed Michael addition followed

Full text of DOI:10.1021/acs.orglett.5b00554

Letter
pubs.acs.org/OrgLett
Synthesis of Functionalized Alkylidene Indanes and Indanones
through Tandem Phosphine−Palladium Catalysis
Yi Chiao Fan and Ohyun Kwon*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
S
* Supporting Information
ABSTRACT: Densely functionalized alkylidene indanes and
indanones can be prepared efficiently in one pot, in high yields
with good stereoselectivities (in some cases exclusively the Z-
isomer), through a route involving phosphine-catalyzed
Michael addition followed by palladium-catalyzed Heck
cyclization. These transformations tolerate substrates bearing
various substituents around the indane/indanone motif.
Employing this technology, a concise formal synthesis of sulindac, a nonsteroidal anti-inflammatory drug, has been established.
irst discovered in the mid-1800s, organocatalysis has
maintained great importance in the synthetic organic
efficient annulation strategy to grant access to these important
indane and indanone compounds. In this Letter, we disclose an
efficient method for synthesizing functionalized indanes and
indanones from 2-iodobenzylmalonates and 2-iodobenzoyl-
acetates.
To test the viability of Michael−Heck annulation in forming
carbocycles, 2-iodobenzylmalonate (1a) was employed to
examine the stepwise Michael addition and Heck cyclization
process (Scheme 1). Using triphenylphosphine as the catalyst,
F
chemistry community.1 Most organocatalysts offer several
attractive features, including minimal environmental impact,
stability to moisture and air, and ready accessibility at low cost.
Of the many established organocatalysts, phosphines are among
the most efficient and versatile, catalyzing many reactions.2 For
many years, however, tertiary phosphines were designed and
used mainly as ligands for transition metal catalysis. It was not
until recently, in the past two decades, that the field of
phosphine catalysis boomed.3 Despite rapid growth in
phosphine catalysis in recent years, examples of tandem
catalysis using both phosphines and transition metals have
remained scarce.
Scheme 1. Stepwise Michael Addition and Heck Cyclization
of 2-Iodobenzylmalonate
Recently, we reported an efficient route for the synthesis of
functionalized alkylidene phthalans using tandem Michael−
Heck cyclization.4 The idea of harnessing the dual reactivities of
the phosphine, as an organocatalyst and as a ligand for
palladium, emerged as a powerful tool for access to phthalan
heterocycles. To further explore the utility of such tandem
phosphine−palladium catalysis, we embarked on the develop-
ment of a simple and efficient method to prepare functionalized
alkylidene indane and indanone carbocycles.
Indanes and indanones are important structural motifs in
molecules of great pharmaceutical significance, displaying, for
example, anti-inflammatory,5 anticancer,6 and antiviral proper-
ties.7 These multifarious bioactivities render both indanes and
indanones as valuable candidates for biological screenings. To
the best of our knowledge, however, there are no examples of
simple transformations for accessing functionalized indanes and
indanones. Conventional methods involving multistep alkyla-
tions,8 Michael additions,9 or Knoevenagel10 condensations
from indanones are not always efficient and offer limited
degrees of functionalization. Other methods, such as intra-
molecular cyclizations, require elaborated disubstituted alkyne
intermediates that may be difficult to access.11−13
the malonate 1a underwent smooth conjugate addition onto
methyl propiolate (2a), producing the desired Michael adduct 3
in excellent yield. The alkylidene indane 4a was then obtained
in good yield after subjecting the enoate 3 to the conditions of a
Heck reaction.14,15
With the success of both these Michael and Heck reactions,
the idea of tandem Michael−Heck annulation was tested
(Scheme 2). Upon completion of the Michael reaction,
palladium was introduced, triggering the subsequent cyclization
As part of a program aimed at advancing nucleophilic
phosphine catalysis, we were prompted to design a simple and
Received: February 23, 2015
Published: April 14, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00554
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Organic Letters
Letter
With optimized conditions in hand, various pronucleophiles
were subjected to the tandem Michael−Heck reaction (Scheme
3). Although other nucleophiles, including the 1,3-dione 4b, the
Scheme 2. Tandem Michael−Heck Annulation of 2-
Iodobenzylmalonate with Methyl Propiolate
a b
,
Scheme 3. Synthesis of Functionalized Alkylidene Indanes
to form the indane 4a. Although the one-pot transformation led
to the desired carbocycle, the reaction yield was only modest.16
Revisiting the stepwise transformations (Scheme 1), the
intramolecular Heck annulation appeared to be the yield-
limiting step. To address this issue and improve the efficiency
of the one-pot process, reaction optimization was performed by
closely examining the Heck cyclization conditions (Table 1).
Table 1. Reaction Optimizations for the Intramolecular
a
Heck Cyclization of Compound 3
b
entry
Pd
PR3
PPh3
additive
yield (%)
1
Pd(OAc)2
Pd(PPh3)2Cl2
PdCl2
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
LiBr
72
71
69
68
67
64
62
63
62
69
73
41
40
43
25
38
79
93
98
2
PPh3
3
PPh3
4
Pd2(dba)3CHCl3
Pd2(dba)3
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(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
5
PPh3
6
P(p-FC6H4)3
P(p-tolyl)3
P(o-furyl)3
PBu3
7
8
a
The acetylene 2 (0.25 mmol) in MeCN (1.0 mL) was added
dropwise to a refluxing solution of the nucleophile 1 (0.1 mmol) and
triphenylphosphine in MeCN (1.0 mL). Upon complete consumption
of 1, Pd(OAc)2, nBu4NOAc (0.1 mmol), and NaHCO3 (0.2 mmol)
were added and the reaction was heated under reflux. The same
conditions were used in the reactions presented in Table 2 and
9
10
11
12
13
14
15
16
17
18
19
DPPE
DPPP
PPh3
PPh3
NH4Cl
b
c
Schemes 4 and 5. Isolated yields and E:Z ratios are given. The E-
isomer was contaminated with a byproduct. See the Supporting
Information (SI) for details.
PPh3
NH4CO3
nEt4NBr
nBu4NI
PPh3
PPh3
PPh3
BnBu3NCl
nBu4NBr
nBu4NOAc
PPh3
β-ketoester 4c, and the malononitrile 4d, were suitable for the
reaction, dimethyl malonate derived pronucleophiles prevailed,
giving excellent yields of the indanes 4a and 4e−k. High
efficiencies were observed when electron-donating substituents
[e.g., methoxy (4e) and methyl (4f and 4g) groups] were
present. The reaction could also tolerate various other
substituents on the benzene ring system. Trifluoromethyl
(4h) and fluoro (4i) groups gave high product yields.
Interestingly, the indanes 4e and 4f were isolated solely as
single Z-stereoisomers. The exclusive Z-selectivity presumably
originated from a nonstereospecific Heck cyclization caused by
the steric bulk of the substituent at the 7-position of the indane.
Such an effect was evident also in the stepwise reactions
(Scheme 1). Additional types of functionalization, using
sterically more demanding benzyl (4j) and tert-butyl propiolate
(4k), also resulted in reactions having good efficiencies.
PPh3
a
A solution of the iodide 3 (0.1 mmol), Pd(OAc)2, triphenylphos-
phine, nBu4NOAc (0.1 mmol), and NaHCO3 (0.2 mmol) in MeCN
b
(2.0 mL) was heated under reflux. The combined yield of the E and Z
isomers was determined through GC analysis using diethyl fumarate as
the internal standard.
The use of different palladium catalysts led to similar reaction
efficiencies (entries 1−5). Testing both electron-deficient and
-rich phosphines led to only minor decreases in yield (entries
6−9). Employing bidentate phosphines, namely 1,2-bis-
(diphenylphosphino)ethane (DPPE) and 1,3-bis(diphenyl-
phosphino)propane (DPPP), did not improve the yield
substantially (entries 10 and 11).17 Changing the salt additive
did, however, have a significant effect on the yield (entries 12−
18). To our delight, an excellent yield was achieved when using
tetra-n-butylammonium acetate as the additive (entry 19).
In addition to the formation of alkylidene indanes, this
methodology can also generate an array of functionalized
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Organic Letters
Letter
indanones when using 2-iodobenzoylacetates as pronucleo-
philes (Scheme 4). Various types of substitution on the
Table 2. Synthesis of Alkylidene Indanones Using Activated
Alkynes
a
Scheme 4. Synthesis of Functionalized Alkylidene
a
Indanones
entry
R
E:Z
yield (%)
1
2
3
4
5
OBn
Ph
1:3
1:1
1:2
1:6
1:3
7a, 97
7b, 51
7c, 53
7d, 55
7e, 88
thienyl
4-NCC6H4
N(OMe)(Me)
a
Isolated yields and E:Z ratios are given. See SI for details.
indanone 7a in excellent yield (entry 1). Although strongly
activated alkynones could be employed in this transformation,
the resulting indanones were obtained in only moderate yields
(entries 2−4). Less-activated propiolamides also participated
with high reaction efficiency (entry 5).
To demonstrate the broad utility of the tandem Michael−
Heck reaction, a concise formal synthesis of sulindac, a
nonsteroidal anti-inflammatory drug, was undertaken (Scheme
5).18 Starting from the β-ketoester 8 and benzyl propiolate
Scheme 5. Synthetic Application of Tandem Michael−Heck
Reaction
a
Isolated yields and E:Z ratios are given. See SI for details.
benzene ring of the indanone were well tolerated. Substrates
bearing electron-donating functionalities [e.g., methoxy (6b),
benzyloxy (6c and 6d), dimethoxy (6e), and methyl (6f and
6g) groups] afforded their products in good to excellent yields.
Those bearing electron-withdrawing moieties [e.g., fluoro (6h),
chloro (6i), and trifluoromethyl (6j) groups] also provided
good to high yields of their indanones. In addition to the α-
methyl-substituted 2-iodobenzoylacetates, the α-butyl-substi-
tuted substrate (5k) also underwent smooth annulation with
high efficiency. Similar to the situation when forming the
indanes, substituents ortho to the iodide group exerted
excellent stereochemical control, leading exclusively to Z-
indanones (6b and 6f).
(2b), the target indanone 9 was produced in good yield. The
formal synthetic target 10 was obtained in high yield through a
hydrogenolysis−decarboxylation−hydrogenation cascade under
the influence of H2 gas and 10% platinum on charcoal.
In conclusion, we have developed a simple and rapid method
that grants access to various functionalized indanes and
indanones from readily accessible 2-iodobenzylmalonates and
2-iodobenzoylacetates and electron-poor alkynes. Furthermore,
this tandem Michael−Heck technology enabled the concise
formal synthesis of sulindac in one step from the indanone 9.
The strategy reported herein may serve as a model for the
design of other tandem phosphine/palladium-catalyzed reac-
tions and may provide new avenues for the efficient synthesis of
compounds of pharmaceutical significance.
Next, various activated alkynes were investigated for their use
in the tandem Michael−Heck reaction (Table 2). Like the
reaction of methyl propiolate (2a), that of the sterically more
congested benzyl propiolate (2b) also afforded its desired
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ASSOCIATED CONTENT
■
S
* Supporting Information
Procedure details and NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ohyun@chem.ucla.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH (R01GM071779) for financial support.
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