Direct synthesis of 1-indanones via pd-catalyzed olefination and ethylene glycol-promoted aldol-type annulation cascade

Article abstract of DOI:10.1021/ol102756m

A wide range of multisubstituted 1-indanones of potential pharmaceutical use were synthesized in a one-pot fashion in moderate to excellent yields via palladium catalysis in ethylene glycol. The Heck reaction first installs an enol functionality on the aromatic ring; this is followed by an ethylene glycol promoted aldol-type annulation with a neighboring carbonyl group, resulting in the formation of various 1-indanones.

Full text of DOI:10.1021/ol102756m

ORGANIC
LETTERS
2011
Vol. 13, No. 2
268-271
Direct Synthesis of 1-Indanones via
Pd-Catalyzed Olefination and Ethylene
Glycol-Promoted Aldol-Type Annulation
Cascade
Jiwu Ruan, Jonathan A. Iggo, and Jianliang Xiao*
Department of Chemistry, UniVersity of LiVerpool, LiVerpool L69 7ZD, U.K.
j.xiao@liV.ac.uk
Received November 13, 2010
ABSTRACT
A wide range of multisubstituted 1-indanones of potential pharmaceutical use were synthesized in a one-pot fashion in moderate to excellent
yields via palladium catalysis in ethylene glycol. The Heck reaction first installs an enol functionality on the aromatic ring; this is followed by
an ethylene glycol promoted aldol-type annulation with a neighboring carbonyl group, resulting in the formation of various 1-indanones.
Indanone and related indan structures constitute the core of
a large number of bioactive natural products and pharma-
ceutically interesting molecules (Figure 1).1 Some represen-
tative examples include the pterosin family, known for their
cytotoxic and antibacterial activities,1b the antihypertensive
drug (+)-Indacrinone,1k the antidepressant Indatraline,1j the
HIV protease inhibitor Indinavir,1i and the acetylcholinest-
erase inhibitor Donepezil (Aricept).1h
In the course of our study into regioselective Heck
reactions,7 we discovered that the Pd(OAc)2-dppp-catalyzed
[dppp ) 1,3-bis(diphenylphosphino)propane] arylation of
Several methods have been reported to access the indanone
framework, including intramolecular Friedel-Craft cyclization,2
hydroacylation of 2-formyl styrenes,3 isomerization of R-aryl-
propargyl alcohols followed by cyclization,4 and other proce-
dures.5 However, most of these require preformed substrates
via multistep synthesis. Recently, Hallberg and Larhed reported
a simple one-pot Heck-aldol annulation reaction between
salicylaldehyde triflates and 2-hydroxy-ethyl vinyl ether, af-
fording indanone ketals in moderate yields.6
Figure 1. Representative examples of indanone and indan-contain-
ing compounds.
10.1021/ol102756m  2011 American Chemical Society
Published on Web 12/16/2010

electron-rich olefins proceeds efficiently in alcohol solvents,
especially ethylene glycol (EG), furnishing branched olefins
in excellent selectivity.7a,b In continuing the research, we
thought that if readily available 2-halobenzaldehydes were
used to arylate the cheap n-butyl vinyl ether, the resulting
branched vinyl ether products might undergo intramolecular
nucleophilic attack at the carbonyl group,8 yielding 1-in-
danones in a one-pot fashion (Scheme 1). To realize this
through hydrogen bonding with the halide anions and the
carbonyl oxygen.9,10 We report herein that 1-indanones can
indeed be readily accessed via this cascade reaction.
Using 2-bromobenzaldehyde (1a) and n-butyl vinyl ether
(2a) as substrates and reaction conditions similar to those
established for other aryl bromides,7b we quickly found that
under the catalysis of Pd-dppp in EG, the indanone (3a) could
be isolated in an excellent yield of 85% following acid
hydrolysis (entry 1, Table 1). To our surprise, however, the
Scheme 1. Working Hypothesis for Accessing 1-Indanones
Table 1. Screening Reaction Conditions for the Cascade
Reactiona
entry
Pd(OAc)2 (mol %)
solvent
yield (%)b
1
2
1
1
2
2
2
EG
EG
DMF
DMF
DMSO
85
86c
<5
42
<5
seemingly easy, Heck-aldol-type cascade, the use of EG as
solvent could be the key, as it would be expected to facilitate
both the Heck arylation7a,b and the nucleophilic attack
3
4d
5
a Reaction conditions: (1) 1a (1 mmol), 2a (3 mmol), Pd(OAc)2 (1 mol
%), dppp (1.5 mol %), Et3N (1.5 mmol), solvent (4 mL), 115 °C, 16 h; (2)
3 M HCl, rt, 1 h. b Isolated yields of 3a. c No acid hydrolysis; isolated
(1) (a) Mahalingam, A. K.; Axelsson, L.; Ekegren, J. K.; Wannberg, J.;
Kihlstro¨m, J.; Unge, T.; Wallberg, H.; Samuelsson, B.; Larhed, M.; Hallberg,
A. J. Med. Chem. 2010, 53, 607. (b) Wessig, P.; Teubner, J. Synlett 2006,
1543, and references therein. (c) Ito, T.; Tanaka, T.; Iinuma, M.; Nakaya,
K.; Takahashi, Y.; Sawa, R.; Murata, J.; Darnaedi, D. J. Nat. Prod. 2004,
67, 932. (d) Yao, W.; Wasserman, Z. R.; Chao, M.; Reddy, G.; Shi, E.;
Liu, R.-Q.; Covington, M. B.; Arner, E. C.; Pratta, M. A.; Tortorella, M.;
Magolda, R. L.; Newton, R.; Qian, M.; Ribadeneira, M. D.; Christ, D.;
Wexler, R. R.; Decicco, C. P. J. Med. Chem. 2001, 44, 3347. (e) Nagle,
D. G.; Zhou, Y.-D.; Park, P. U.; Paul, V. J.; Rajbhandari, I.; Duncan,
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S. Org. Prep. Proced. Int. 1999, 31, 1. (g) Lago, M. A.; Luengo, J. I.;
Peishoff, C. E.; Elliot, J. D. In Annuual Reports in Medicinal Chemistry;
Bristol, J. A., Ed.; Academic Press: San Diego, 1996; Vol. 31, p 81. (h)
Sugimoto, H.; Iimura, Y.; Yamanishi, Y.; Yamatsu, K. J. Med. Chem. 1995,
38, 4821. (i) Dorsey, B. D.; Levin, R. B.; McDaniel, S. L.; Vacca, J. P.;
Guare, J. P.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.;
Quintero, J. C.; Lin, J. H.; Chen, I.-W.; Holloway, M. K.; Fitzgerald,
P. M. D.; Axel, M. G.; Ostovic, D.; Anderson, P. S.; Huff, J. R. J. Med.
Chem. 1994, 37, 3443. (j) Bøgesø, K. P.; Christensen, A. V.; Hyttel, J.;
Liljefors, T. J. Med. Chem. 1985, 28, 1817. (k) deSolms, S. J.; Woltersdorf,
O. W., Jr.; Cragoe, E. J., Jr. J. Med. Chem. 1978, 21, 437.
d
yields of 3aa. 1.5 mmol [H2NiPr2][BF4] was added.
indanone ketal (3aa) was isolated in 86% yield when the
acid treatment was omitted (entry 2), indicative of 3a being
formed from 3aa. Apart from the mechanistic implication,
this provides a simple method for synthesizing ketal-
protected indanones, which were obtained in moderate yields
via Hallberg and Larhed’s method.6a For comparison, the
reaction was also performed in DMF and DMSO. As can
be seen from Table 1, little desired product was formed
(entries 3 and 5), most likely due to the Heck arylation being
sluggish.7a,b Introducing the hydrogen bond donor
[H2NiPr2][BF4], which has been shown to promote the Heck
reaction,7d led to an increased but still unsatisfactory yield
of 42% for 3a (entry 4), indicating that EG is highly effective
in catalyzing both the Heck and annulation reactions.
Under the reaction conditions established above (entry 1,
Table 1), we then explored the reactions of 2a with a range
of 2-bromobenzaldehydes (1a-h). As summarized in Table
2, the reaction afforded good to excellent yields of 3-hy-
droxy-1-indanones (3a-h), tolerating electronically different
substituents on the aromatic ring. However, when salicyla-
ldehyde triflate was used,6 3a was obtained only in 12%
yield, due to decomposition of the triflate in EG.
(2) For recent examples, see: (a) Cui, D.-M.; Zhang, C.; Kawamura,
M.; Shimada, S. Tetrahedron Lett. 2004, 45, 1741. (b) Fillion, E.; Fishlock,
D.; Wilsily, A.; Goll, J. M. J. Org. Chem. 2005, 70, 1316, and references
therein.
(3) Kundu, K.; McCullagh, J. V.; Morehead, A. T. J. Am. Chem. Soc.
2005, 127, 16042.
(4) (a) Shintani, R.; Yashio, K.; Nakamura, T.; Okamoto, K.; Shimada,
T.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 2772. (b) Shintani, R.; Takatsu,
K.; Hayashi, T. Angew. Chem., Int. Ed. 2007, 46, 3735.
(5) (a) Gagnier, S. V.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 4804.
(b) Matsuda, T.; Shigeno, M.; Makino, M.; Murakami, M. Org. Lett. 2006,
8, 3379. (c) Minatti, A.; Zheng, X.; Buchwald, S. L. J. Org. Chem. 2007,
72, 9253. (d) Petrignet, J.; Roisnel, T.; Gre´e, R. Chem.sEur. J. 2007, 13,
7374. (e) Saito, A.; Umakoshi, M.; Yagyu, N.; Hanzawa, Y. Org. Lett.
2008, 10, 1783.
(6) (a) Bengtson, A.; Larhed, M.; Hallberg, A. J. Org. Chem. 2002, 67,
5854. (b) Arefalk, A.; Larhed, M.; Hallberg, A. J. Org. Chem. 2005, 70,
938.
With the success in aryl bromides, we turned our attention
to the chloride analogues. However, under the same condi-
(7) (a) Ruan, J.; Iggo, J. A.; Berry, N. G.; Xiao, J. J. Am. Chem. Soc.
2010, 132, 16689. (b) Zeynab, H.; Ruan, J.; Xiao, J. Chem.sEur. J. 2008,
14, 5555. (c) Ruan, J.; Saidi, O.; Iggo, J. A.; Xiao, J. J. Am. Chem. Soc.
2008, 130, 10510. (d) Mo, J.; Xiao, J. Angew. Chem., Int. Ed. 2006, 45,
4152. (e) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751.
(8) For intermolecular aldol-type reactions of vinyl ethers, see: Carreira,
E. M.; Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995, 117, 3649.
(9) Ethylene glycol is an excellent hydrogen bond donor: Reichardt, C.
SolVents and SolVent Effects in Organic Chemistry, 3rd ed.; Wiley-VCH:
Weinheim, 2003.
(10) The carbonyl may be activated through a single-point hydrogen
bonding; see ref 7a. Also see: Unni, A. K.; Takenaka, N.; Yamamoto, H.;
Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336.
Org. Lett., Vol. 13, No. 2, 2011
269

Table 2. Heck-Aldol Annulation Reaction of ArBr (1a-h)
with n-Butyl Vinyl Ether (2a)a
Table 3. Heck-Aldol Annulation of ArCl (1i-q) with 2aa
a Reaction conditions: (1) 1 (1 mmol), 2a (3 mmol), Pd(OAc)2 (1 mol
%), dppp (1.5 mol %), Et3N (1.5 mmol), EG (4 mL), 115 °C, 16 h; (2) 3
M HCl, rt, 1 h. b Isolated yields.
a Reaction conditions: (1) 1i-q (1 mmol), 2a (3 mmol), Pd(OAc)2 (2
mol %), 4-MeO-dppp (3 mol %), Et3N (1.5 mmol), EG (4 mL), 145 °C,
16 h; (2) 3 M HCl, rt, 1 h. b Isolated yields.
tions as those for the bromides, the reaction of 2-chloroben-
zaldehyde (1i) with 2a led to only 6% of indanone 3a. A
slightly higher yield of 15% was obtained at 145 °C. We
have recently shown that the Pd(OAc)2-4-MeO-dppp system
[4-MeO-dppp ) 1,3-bis(bis(4-methoxyphenyl)phosphino-
)propane] is very efficient for the Heck arylation with various
aryl chlorides in EG.7a Bearing this in mind, we changed
the ligand from dppp to 4-MeO-dppp and were gratified to
obtain 3a in 70% isolated yield at 145 °C at a catalyst loading
of 2 mol % (entry 1, Table 3). The yield (55%) was lower
at 115 °C. Subsequently, other substituted 2-chlorobenzal-
dehydes 1j-q were examined. The results are shown in
Table 3. As can be seen, moderate to good yields of
indanones 3 were obtained, albeit slightly lower than those
from the bromides. Worthy of noting is that the sterically
more demanding substrates 1j and 1o-q successfully
underwent the Heck-annulation cascade, affording good
yields (entries 2, 7-9). Also of interest is that 6-chloro-3-
hydroxy-1-indanone 3j was formed in 50% yield (entry 4),
showing that the sterically less accessible ortho-chloride is
more reactive when using 2,4-dichlorobenzaldehyde (1l).
To extend further the substrate scope, we next investigated
the reaction of a bulkier vinyl ether, 1-ethoxyprop-1-ene (2b),
with various 2-halobenzaldehydes 1 under the same condi-
tions for the respective halides. These reactions required a
longer reaction time of 20 h, however. As shown in Table
4, a range of 2-methyl-3-hydroxy-1-indanones 4a-e were
produced in moderate yields, as a mixture of cis- and trans-
isomers. The reaction provides a straightforward way for the
total synthesis of pterosins.1b
2′-Haloaryl ketones were also demonstrated to be viable
substrates, affording quaternary alcohols (Table 5). Using the
ketones 5a-g as substrates, 3-hydroxy-1-indanones 6a-d were
obtained in moderate to good yields; even the bulky 2′-bromo-
or 2′-chlorobenzophenones underwent the annulation (entries
3 and 7). There are only a few methods for synthesizing 3,3′-
270
Org. Lett., Vol. 13, No. 2, 2011

Table 4. Heck-Aldol Annulation of ArX with
1-Ethoxyprop-1-ene (2b)a
Table 5. Heck-Aldol Annulation of 2′-Haloaryl Ketones
(5a-g) with 2aa
a The reaction conditions were the same as those in Table 2 for aryl
bromides and Table 3 for aryl chlorides, except for using 2b and 20 h
reaction time. b Isolated yields.
a The reaction conditions were the same as those in Table 4. b Isolated
yields.
disubstituted 1-indanones,2b,4b,5b and to the best of our
knowledge, this is the first time that 1-indanones bearing a
quaternary 3-hydroxy functionality have been reported.
As aforementioned, the reaction of 1a with 2a in EG led
to 3aa being isolated in high yield, instead of the cyclic enol
ether shown in Scheme 1, if acid hydrolysis was not
performed (entry 2, Table 1). Taking this into account, a
mechanism for the cascade reaction is suggested (Scheme
2). The Heck reaction affords the branched enol ether
product, which undergoes nucleophilic attack at the carbonyl
group activated by EG via hydrogen bonding.9,10 The
resulting oxonium ion reacts with EG, giving rise to a mixed
ketal. Elimination of BuOH under acid catalysis then leads
to 3aa, and finally, acidic treatment of 3aa forms 3a. Similar
mixed and cyclic ketals have previously been observed when
the Heck reaction was run in diols.11
Scheme 2
.
Suggested Mechanism for the Heck-Aldol
Annulation
In summary, we have developed a new protocol for the
one-pot synthesis of pharmaceutically interesting, multisub-
stituted 1-indanones. The protocol centers on a Heck-aldol
cascade, with Pd catalyzing the Heck arylation while EG
facilitates both the arylation and the aldol-type annulation.
Further study into the mechanism and enantioselective
synthesis of 3-hydroxy-1-indanones is underway.
Acknowledgment. The authors thank the EPSRC (EP/
F000316) for support.
Supporting Information Available: Experimental details
and characterization data of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) McConville, M.; Blacker, J.; Xiao, J. Synthesis 2010, 349.
Org. Lett., Vol. 13, No. 2, 2011
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