Convenient Access to Polysubstituted 1-Indanones by Sc(OTf) 3-Catalyzed Intramolecular Friedel-Crafts Acylation of Benzyl Meldrum's Acid Derivatives

Article abstract of DOI:10.1021/ol035817m

(Matrix presented) The intramolecular Friedel-Crafts acylation of benzyl Meldrum's acids is catalyzed by Sc(OTf)₃ under mild reaction conditions. Several polysubstituted 1-indanones have been prepared.

Full text of DOI:10.1021/ol035817m

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4653-4656
Convenient Access to Polysubstituted
1-Indanones by Sc(OTf)3-Catalyzed
Intramolecular Friedel−Crafts Acylation
of Benzyl Meldrum’s Acid Derivatives
Eric Fillion* and Dan Fishlock
Department of Chemistry, UniVersity of Waterloo, Waterloo,
Ontario N2L 3G1, Canada
efillion@uwaterloo.ca
Received September 20, 2003
ABSTRACT
The intramolecular Friedel−Crafts acylation of benzyl Meldrum’s acids is catalyzed by Sc(OTf)3 under mild reaction conditions. Several
polysubstituted 1-indanones have been prepared.
The intramolecular Friedel-Crafts reaction is a general and
convenient method for the synthesis of 1-indanones, 1-tetra-
lones, and related aromatic ketones.1 Such carbocycles have
proven synthetic utility in numerous pharmaceuticals and
biologically active natural products.2 The importance of this
transformation has generated great interest in the develop-
ment of a catalytic Friedel-Crafts acylation under mild
reaction conditions.
Despite considerable progress made in the development
of Lewis acid catalyzed protocols,3 the cyclization precursors
are essentially limited to carboxylic acids and acid chlorides.4
Progress toward a truly mild and operationally simple
Friedel-Crafts reaction would be aided by the availability
of a moisture-stable, highly electrophilic precursor that is
easily prepared, functionalized, and purified, preferably by
recrystallization. Friedel-Crafts acylation of such a precursor
should provide aromatic ketones catalytically at moderate
temperatures and be sufficiently flexible to assemble poly-
cyclic ring systems rapidly and modify substitution within
the rings.
Meldum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) is a
versatile reagent that can be easily functionalized at the
5-position.5 It is highly susceptible to nucleophilic attack at
the carbonyl carbons. As illustrated in Scheme 1, the aryla-
Scheme 1. Meldrum’s Acid Derivatives in the Lewis Acid
Catalyzed Intramolecular Friedel-Crafts Acylation
(1) (a) Olah, G. Friedel-Crafts Chemistry; Wiley-Interscience: New
York, 1973. (b) Heaney, H. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 733-
752 and 753-768.
(2) (a) Gagnier, S. V.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 4804-
4807. (b) Adams, D. R.; Duncton, M. A. J. Synth. Commun. 2001, 31, 2029-
2036. (c) Bo¨s, M.; Jenck, F.; Martin, J. R.; Moreau, J.-L.; Sleight, A. J.;
Wichmann, J.; Widmer, U. J. Med. Chem. 1997, 40, 2762-2769. (d)
Sugimoto, H.; Iimura, Y.; Yamanishi, Y.; Yamatsu, K. J. Med. Chem. 1995,
38, 4821-4829.
(3) For rare earth triflate catalysts in the intramolecular Friedel-Crafts
reaction of aromatics with carboxylic acids, see: (a) Cui, D.-M.; Kawamura,
M.; Shimada, S.; Hayashi, T.; Tanaka, M. Tetrahedron Lett. 2003, 44,
4007-4010. For an example of protic acid-catalyzed Friedel-Crafts
acylation, see: (b) Yamato, T.; Hideshima, C.; Prakash, G. K. S.; Olah, G.
A. J. Org. Chem. 1991, 56, 3955-3957.
tion of Meldrum’s acid derivatives would lead to inert side
products: CO2 and acetone.6 Exploiting the high electro-
philicity, stability, easy access, and purification of Meldrum’s
acid derivatives, we herein report an intramolecular Friedel-
10.1021/ol035817m CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/23/2003

Crafts acylation protocol of benzyl Meldrum’s acid deriva-
tives catalyzed by Sc(OTf)3 under mild reaction conditions.
This method has been applied to the synthesis of polysub-
stituted 1-indanones.
Simple and versatile routes gave access to the Friedel-
Crafts acylation precursors in one or two steps from
Meldrum’s acid (Scheme 2). A method was developed to
The intramolecular acylation of arenes with Meldrum’s
acid derivatives was initiated with the electron-rich 3,5-
dimethoxybenzene substrate 1a searching for effective cata-
lyst and reaction conditions. The Friedel-Crafts acylation
of 1a proceeded in refluxing CH3NO2 in the absence of
catalyst and provided indanone 2a in 52% yield (Table 1,
Table 1. Effect of Catalysts on the Acylation Reaction of 1a
Scheme 2. Meldrum’s Acid Derivatives Synthesis
reaction
time (h)
yield
(%)
entry
catalyst
solvent
1
2
3
4
5
6
7
8
9
CH3NO2
3
2.75
17
3
1
1
4.5
2
1
52
38
37
60
56
67
72
68
73
TfOH (20 mol %)
TFA (20 mol %)
TMSOTf (20 mol %)
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
Dy(OTf)3 (12 mol %) CH3NO2
Yb(OTf)3 (12 mol %) CH3NO2
Sc(OTf)3 (10 mol %)
Sc(OTf)3 (8 mol %)
Sc(OTf)3 (12 mol %)
ClCH2CH2Cl
CH3CN
CH3NO2
entry 1). Attempts at improving the yield using protic acids
in refluxing polar solvents failed (Table 1, entries 2-3), and
3-(3,5-dimethoxyphenyl)propanoic acid was formed as the
major product. Indanone 2a was isolated in good yield when
1a was treated with TMSOTf (entry 4).
We next examined rare earth triflates, which have been
reported to efficiently catalyze the intermolecular Friedel-
Crafts acylation reaction of activated aromatics with anhy-
drides.10 Dy(OTf)3 was inefficient at improving the yield,
but Yb(OTf)3 enhanced the formation of 2a, while decreasing
reaction time (Table 1, entries 5 and 6). Indanone 2a was
obtained in 68-73% yield using 8-12 mol % of Sc(OTf)3
in CH3NO2, CH3CN, or ClCH2CH2Cl. In comparison with
the thermal and TMSOTf-catalyzed acylations, the crude
reaction mixture was cleaner and the product easy to isolate
and purify.11
prepare the methylene tethered Meldrum’s acid derivatives
by reductive alkylation. Substituted benzaldehydes were
condensed with Meldrum’s acid and the resulting alkylidene
were reduced in situ with NaBH3CN.7 Mono- and disubsti-
tuted Meldrum’s acid derivatives at the benzylic position
were accessed via 1,4-conjugate addition of aryl Grignards
to Meldrum’s alkylidenes,8 prepared by Knoevenagel con-
densation of Meldrum’s acid with ketones.9 The overall
yields for the acylation precursor syntheses, which were
prepared on multigram scale due to the availability of the
starting materials, varied from good to modest. In most cases,
the Meldrum’s acid derivatives were purified by recrystal-
lization.
Using Sc(OTf)3 in refluxing CH3NO2 or CH3CN as the
standard reaction conditions, the influence of substitution at
the benzylic position on the acylation efficiency was exam-
ined (Table 2). Increased substitution improved the efficiency
of the acylation reaction, and good yields (77-83%) of
3-substituted 2b (entry 1) and 3,3-disubstituted-1-indanones
2c and 2d were obtained (entries 2 and 3). This effect was
(4) Larock, R. C. ComprehensiVe Organic Transformations, 2nd ed.;
Wiley-VCH: New York, 1999; pp 1422-1433.
(5) (a) Chen, B.-C. Heterocycles 1991, 32, 529-597. (b) McNab, H.
Chem. Soc. ReV. 1978, 7, 345-358.
(6) The pyrolysis of 2,2-dimethyl-5-phenoxy-1,3-dioxane-4,6-dione at
450 °C provides a small amount of benzofuran-2(3H)-one via a proposed
phenoxyketene intermediate; see: Crow, W. D.; McNab, H. Aust. J. Chem.
1979, 32, 111-121.
(7) For other reductive alkylation procedures, see: (a) Huang, X.; Xie,
L. Synth. Commun. 1986, 16, 1701-1707. (b) Hrubowchak, D. M.; Smith,
F. X. Tetrahedron Lett. 1983, 24, 4951-4954.
(8) (a) Vogt, P. F.; Molino, B. F.; Robichaud, A. J. Synth. Commun.
2001, 31, 679-684. (b) Davies, A. P.; Egan, T. J.; Orchard, M. G.;
Cunningham, D.; McArdle, P. Tetrahedron 1992, 48, 8725-8738. (c)
Larcheveˆque, M.; Tamagnan, G.; Petit, Y. J. Chem. Soc., Chem. Commun.
1989, 31-33. (d) Huang, X.; Chan, C.-C.; Wu, Q.-L. Synth. React. Inorg.
Met.-Org. Chem. 1982, 12, 549-556. (e) Huang, X.; Chan, C.-C.; Wu,
Q.-L. Tetrahedron Lett. 1982, 23, 75-76. (f) Haslego, M. L.; Smith, F. X.
Synth. Commun. 1980, 10, 421-427.
(10) (a) Kawada, A.; Mitamura, S.; Matsuo, J.-i.; Tsuchiya, T.; Koba-
yashi, S. Bull. Chem. Soc. Jpn. 2000, 73, 2325-2333. (b) For a recent
review, see: Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L.
Chem. ReV. 2002, 102, 2227-2302.
(11) To determine if the byproduct acetone was causing side reactions
that were decreasing the yield of the Friedel-Crafts acylation, a control
reaction was performed by refluxing an equimolar amount of 1-indanone
and acetone in the presence of a catalytic amount of Sc(OTf)3 for 1 h. GC-
MS and 1H NMR analysis of the crude reaction mixture showed no
decomposition of 1-indanone or formation of aldol products.
(9) Baty, J. D.; Jones, G.; Moore, C. J. Org. Chem. 1969, 34, 3295-
3302.
4654
Org. Lett., Vol. 5, No. 24, 2003

Table 2. Acylation of 3,5-Disubstituted Arenes
Table 3. Acylation of 3-Mono- and Unsubstituted Arenes
reaction
time (h)
products
(ratio)a
yield
(%)
reaction
yield
(%)
entry
1
substrate
entry
1
substrate
time (h)
product
3a , R1 ) OMe;
R2 ) H
3b, R1 ) OMe;
R2 ) -(CH2)5-
3c, R1 ) Me;
R2 ) H
3d , R1 ) Me;
R2 ) -(CH2)5-
3e, R1 ) Cl;
R2 ) H
3f, R1 ) Cl;
R2 ) -(CH2)5-
3g, R1 ) R2 ) H
3h , R1 ) H;
R2 ) -(CH2)5-
1
2
1
2
2
2
4a /5a (5.5:1)
4b/5b (3.4:1)
4c/5c (1:1)
52
1b, R1 ) R2 ) OMe;
R3 ) Me; R4 ) H
1c, R1 ) R2 ) OMe;
R3 ) R4 ) Me
1d , R1 ) R2 ) OMe;
R3 ) R4 ) -(CH2)5-
1e, R1 ) R2 ) Me;
R3 ) R4 ) H
2
2b
77
2
3
4
5
6
71
2
3
4
5
2
2c
2d
2e
2f
82
48
2
83
9
52a
75a
4d /5d (1:1)
62
trace
62
1f, R1 ) R2 ) Me;
R3 ) R4 ) -(CH2)5-
1.5
4e/5e (2:1)
a The reaction was run in CH3NO2.
7
8
9
0.5
4f
13b
56c
4g
more pronounced for the 3,5-dimethylbenzene substrates than
for the dimethoxy compounds (entries 4 and 5), but
comparable yields were observed when the benzylic position
was disubstituted (entries 3 and 5). Slow addition of the
substrate to a solution of the Lewis acid did not improve
the acylation yield for substrate 1f (9-h slow addition gave
2f in 73%). However, when indanone 2e was prepared using
the slow addition procedure, the yield was enhanced from
36% to 52%.
Having established the reactivity of Meldrum’s acid
derivatives with π-nucleophiles in the presence of Sc(OTf)3,
this acylation protocol was applied to mono- and unsubsti-
tuted aromatics. The importance of substitution at the ben-
zylic position was prominent for substrates bearing a weak
π-nucleophilic moiety12 (Table 3). Regioisomeric indanones
4a and 5a were obtained from the monomethoxy substrates
3a in modest yield (Table 3, entry 1). In comparison, disub-
stituted substrate 3b gave a respectable yield of indanones
4b and 5b.
Substrate 3g gave a low 13% yield of 1-indanone 4f using
the slow addition protocol, but the disubstituted substrate
3h yielded 56% of 4g under the standard conditions. Friedel-
Crafts acylation of 3h in the absence of Sc(OTf)3 provided
no trace of indanone after 24 h in refluxing CH3NO2,
returning starting material.
A similar trend was observed for the cyclization of 3c and
3d. Deactivated m-chloro substrate 3f provided a mixture
of indanones 4e and 5e in 62% yield. Without any benzylic
substituent, only trace formation of 1-indanone was detected
using the slow addition method with substrate 3e.
Three plausible reaction pathways for the intramolecular
reaction of benzyl Meldrum’s acid derivatives are illustrated
in Scheme 3. Initial activation of the Meldrum’s acid car-
bonyl group by Sc(OTf)3 is key in all three pathways.
a Determined by analysis of the crude 1H NMR. b Substrate 3g was added
over 9 h to a refluxing solution of Sc(OTf)3 by syringe pump, followed by
an additional 2 h of reflux. The one-pot procedure failed to produce indanone
4f. c A yield of 57% was obtained when the slow addition procedure was
used.
In Scheme 3 (reaction pathway a), Sc(OTf)3 promotes
tautomerization of benzyl Meldum’s acid derivative to the
corresponding 6-hydroxydioxinone. Enolized Meldrum’s
acids have been reported to cyclorevert leading to highly
electrophilic acylketene intermediates.13,14 Arylation of the
Lewis acid activated acylketene yields an 1-indanone-2-
carboxylic acid that further decarboxylates.15
The Lewis acid activated Meldrum’s acid could directly
participate in the acylation process as depicted in Scheme 3
(reaction pathway b). Following acylation, subsequent loss
of acetone and CO2 provides the indanone. This pathway
parallels the conventional Friedel-Crafts acylation of arenes
with anhydrides and acid chlorides.1
Finally, Meldrum’s acid ring-opening reaction accompa-
nied by the loss of acetone and CO2 generates a ketene
(Scheme 3, reaction pathway c) that further participates in
the acylation process.16
Investigation of reaction pathway a proceeded by methy-
lation of 1a with Meerwein’s salt to produce an R-oxoketene
(13) (a) Sato, M.; Bann, H.; Kaneko, C. Tetrahedron Lett. 1997, 38,
6689-6692. (b) Bihlmayer, G. A.; Schuster, P.; Polansky, O. E. Monatsh.
Chem. 1966, 97, 145-149.
(14) For a review on R-oxoketenes, see: Wentrup, C.; Heilmayer, W.;
Kollenz, G. Synthesis 1994, 1219-1248.
(15) (a) For an example of Friedel-Crafts acylation of chromium-
carbene-complex-derived ketenes catalyzed by ZnCl2, see: Bueno, A. B.;
Moser, W. H.; Hegedus, L. S. J. Org. Chem. 1998, 63, 1462-1466. For
intermolecular Friedel-Crafts arylation of ketenes, see: (b) Williams, J.
W.; Osborn, J. M. J. Am. Chem. Soc. 1939, 61, 3438-3439. (c) Hurd, C.
J. Am. Chem. Soc. 1925, 47, 2777-2780.
(12) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-
77.
(16) Gaber, A. E.-A. O.; McNab, H. Synthesis 2001, 2059-2074.
Org. Lett., Vol. 5, No. 24, 2003
4655

Scheme 3. Proposed Reaction Pathways
Scheme 4. Studies on the Acylation Mechanism
taneously proceed via any of the three pathways. The
important yield enhancement when the Meldrum’s acid
substrate is substituted at the benzylic position may be an
indication that the acylation occurs via a ketene intermediate.
R-Substitution has been demonstrated to significantly in-
crease the stability of R-oxoketenes.13a
In conclusion, we have disclosed a mild and catalytic
procedure for the intramolecular Friedel-Crafts acylation
of aromatics with Meldrum’s acids. The present protocol has
some advantages over the existing methods in term of
operational simplicity, preparation, and versatility of the
cyclization precursors and 1-indanones. Further research is
ongoing to apply this method to other systems and establish
the reaction mechanism.
intermediate via cycloreversion of the resulting 6-methoxy-
dioxinone. Intramolecular arylation of the acylketene inter-
mediate was anticipated to produce a â-ketoester incapable
of decarboxylation. Gratifyingly, 1-indanone-2-methyl ester
6a was formed in 52% yield demonstrating the reactivity of
acylketenes in acylation reactions (Scheme 4). Similarly,
disubstituted substrate 1d gave indanone 6b.
In an attempt to suppress reaction pathway a, the non-
enolizable substrate 7 was subjected to the optimized reaction
conditions (Scheme 4). Efficient formation of 2-methyl-1-
indanone 8 in 80% yield was realized,17 supporting reaction
pathways b and c in Scheme 3. Enolization of Meldrum’s
acid derivatives is therefore not a prerequisite for the
acylation to proceed.
Acknowledgment. The Natural Science and Engineering
Research Council of Canada and the University of Waterloo
are thanked for financial support. D.F. thanks the Govern-
ment of Ontario for a fellowship (OGSST). Andrew Martins
is acknowledged for preliminary experiments.
Supporting Information Available: Experimental pro-
cedures and characterization for compounds 2a-f, 4a-g,
5a-e, 6a,b, and 8. This material is available free of charge
via the Internet at http://pubs.acs.org.
At this point, the reaction mechanisms have not been
differentiated, and the overall acylation process may simul-
(17) In the absence of Sc(OTf)3, the starting material was quantitatively
recovered.
OL035817M
4656
Org. Lett., Vol. 5, No. 24, 2003