Indanones and indenols from 2-alkylcinnamaldehydes via the intramolecular friedel-crafts reaction of geminal diacetates

Article abstract of DOI:10.1021/jo900910b

(Figure Presented) When treated with Ac₂O at rt in the presence of 4-6mol% FeCl₃, 2-alkylcinnamaldehydes are converted to 2-alkyl-1H-inden-1-yl acetates through the intermediacy of gem-diacetates. Methanolysis of the indenyl acetates

Full text of DOI:10.1021/jo900910b

pubs.acs.org/joc
as aldehyde protecting groups.2,4 Other synthetic uses are
Indanones and Indenols from
2-Alkylcinnamaldehydes via the Intramolecular
Friedel-Crafts Reaction of Geminal Diacetates
concerned mainly with substitution reactions of a carbox-
ylate group with carbon nucleophiles.1,5 Acetic acid elimina-
tion from the diacetate acylals of R,β-unsaturated aldehydes
produces 1-acetoxy-1,3-dienes, which have been used in
Diels-Alder reactions.6 Acylals of R,β-unsaturated alde-
hydes also have been employed as substrates in Pd-catalyzed
allylic substitutions.7 In the presence of Lewis acids, the
acylals of acrolein and 2-alkylacroleins will alkylate aro-
matic rings, yielding the enol acetates of 3-arylpropanals, the
Scriabine reaction.8 This reaction, which provides a route to
3-arylpropanals, was described by Igor Scriabine in 1961.
The transformation was effected by treating the unsaturated
acylals with an excess of arene and 1 equiv of TiCl4 in
Gary B. Womack,* John G. Angeles, Vincent E. Fanelli,
Brinda Indradas, Roger L. Snowden, and Philippe Sonnay
Corporate R&D Division, Firmenich, Inc., P.O. Box 5880,
Princeton, New Jersey 08543
gary.womack@firmenich.com
Received May 1, 2009
combination with BF3 Et2O. More recent procedures devel-
oped for industrial purposes accomplish the reaction using
substoichiometric levels of Lewis acid.8e,8f
3
Recently, we reported that in situ generated dimethyl
acetals of (E)-2-alkylcinnamaldehydes cyclize in the presence
of catalytic quantities of FeCl3, yielding 1-alkoxy-2-alkyl-
1H-indenes (1).9,10 Typically, indene formation was effected
using 5-10 mol % FeCl3 in refluxing MeOAc. These indenes
were then transformed in two steps (base-catalyzed double-
bond migration to form the enol ether and acid-catalyzed
hydrolysis) into 2-alkylindanones (2). Formally, the trans-
formation corresponds to an intramolecular Friedel-Crafts
acylation achieved with catalytic quantities of Lewis acid.11
Traditional Friedel-Crafts acylations require stoichio-
metric amounts of Lewis acid to proceed to completion
because of coordination of Lewis acid with the resulting aryl
ketones. On the basis of the precedents of our acetal cycliza-
tion and the Scriabine reaction, it seemed plausible that
When treated with Ac2O at rt in the presence of 4-6 mol %
FeCl3, 2-alkylcinnamaldehydes are converted to 2-alkyl-
1H-inden-1-yl acetates through the intermediacy of gem-
diacetates. Methanolysis of the indenyl acetates yields the
corresponding indenols. Saponification yields 2-alkylinda-
nones, providing, in effect, an intramolecular acylation
employing catalytic levels of acid.
Geminal dicarboxylates, or acylals, are prepared by the
acid-catalyzed reaction between aldehydes and noncyclic
anhydrides of carboxylic acids. The reaction is easily accom-
plished under mild conditions using a variety of Brønsted or
Lewis acid catalysts.1,2 A convenient, solventless procedure
is to treat aldehydes with excess acetic anhydride and cata-
lytic quantities of FeCl3 at 0 °C.3 Acylals have been proposed
(6) (a) Snider, B. B.; Amin, S. G. Synth. Commun. 1978, 8, 117–125.
(b) Banks, R. E.; Miller, J. A.; Nunn, M. J.; Stanley, P.; Weakley, T. J. R.;
Zakir, U. J. Chem. Soc., Perkin Trans. 1 1981, 1096–1102. (c) Blanc, P.-Y.
Helv. Chim. Acta 1961, 44, 1–12.
(7) (a) Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 2001, 123, 3671–3686.
(b) Trost, B. M.; Crawley, M. L.; Lee, C. B. Chem.;Eur. J. 2006, 12, 2171–
2187. (c) Trost, B. M.; Lee, C. B.; Weiss, J. M. J. Am. Chem. Soc. 1995, 117,
7247–7248. (d) Trost, B. M.; Vercauteren, J. Tetrahedron Lett. 1985, 26, 131–
134. (e) Nay, B.; Peyrat, J.-F.; Vercauteren, J. Eur. J. Org. Chem. 1999, 2231–
2234. (f) Lu, X.; Huang, Y. J. Organomet. Chem. 1984, 268, 185–190. (g)
Gravel, D.; Benoit, S.; Kumanovic, S.; Sivaramakrishnan, H. Tetrahedron
Lett. 1992, 33, 1403–1406. (h) van Heerden, F. R.; Huyser, J. J.; Williams, D.
B. G.; Holzapfel, C. W. Tetrahedron Lett. 1998, 39, 5281–5384.
(8) (a) Scriabine, I. Bull. Chem. Soc. Fr. 1961, 1194–1198. (b) Hurlbert, B.
S.; Valenti, B. F. J. Med. Chem. 1968, 11, 708–710. (c) Skouroumounis, G.;
Winter, B. Helv. Chim. Acta 1996, 79, 1095–1109. (d) Valentine, R. H.;
Brandman, H. A. Process for the Preparation of Dihydrocinnamaldehyde
Derivatives. U.S. Patent 4,389,527, June 21, 1983. (e) Shirai, M.; Yoshida, Y.
Sadaike, S. Process for Producing 1-Acetoxy-3-(substituted phenyl)propene
Compound. U.S. Patent 7,173,148 B2, Feb 6, 2007. (f) Snowden, R. L.; Birkbeck,
A.; Womack, G. B. Catalytic Scriabine Reaction. U.S. Patent Appl. 2008/0091042
A1, April 17, 2008.
(1) For a review of the acylal preparation and chemistry, see: Sydnes, L.
K.; Sandberg, M. PINSA-A: Proc. Indian Natl. Sci. Acad., Part A 2002, 68,
141–174.
(2) For recent examples of acylal preparations, see: (a) Karimi, B.;
Maleki, J. J. Org. Chem. 2003, 68, 4951–4954. (b) Yin, L.; Zhang, Z.-H.;
Wang, Y.-M.; Pang, M.-L. Synlett 2004, 1727–1730. (c) Aggen, D. H.;
Arnold, J. N.; Hayes, P. D.; Smoter, N. J.; Mohan, R. S. Tetrahedron
2004, 60, 3675–3679. (d) Kavala, V.; Patel, B. K. Eur. J. Org. Chem. 2005,
441–451. (e) Wang, J.; Yan, L.; Qian, G.; Yang, K.; Liu, H.; Wang, X.
Tetrahedron Lett. 2006, 47, 8309–8312. (f) Pahman, M. A. F. M.; Jahng, Y.
Eur. J. Org. Chem. 2007, 379–383. (g) Hajipour, A. R.; Zarei, A.; Ruoho, A.
E. Tetrahedron Lett. 2007, 48, 2881–2884. (h) Satam, J. R.; Jayaram, R. V.
Catal. Commun. 2007, 8, 1414–1420. (i) Yadav, J. S.; Reddy, B. V. S.;
Sreedhar, P.; Kondaji, G.; Nagaiah, K. Catal. Commun. 2008, 9, 590–593.
(3) Kochhar, K. S.; Bal, B. S.; Deshpande, R. P.; Rajadhyaksha, S. N.;
Pinnick, H. W. J. Org. Chem. 1983, 48, 1765–1767.
(9) Womack, G. B.; Angeles, J. G.; Fanelli, V. E.; Heyer, C. A. J. Org.
Chem. 2007, 72, 7046–7049.
(10) The formation of 1 has also been reported using a stoichiometric
amount of BF3 Et2O: (a) Jobashi, T.; Kawai, A.; Kawai, S.; Maeyama, K.;
(4) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1999; pp 184-185.
3
Oike, H.; Yoshida, Y.; Yonezawa, N. Tetrahedron 2006, 62, 5717–5724.
(b) Jobashi, T.; Maeyama, K.; Noguchi, K.; Yoshida, Y.; Yonezawa, N. Bull.
Chem. Soc. Jpn. 2006, 79, 627–633.
(5) (a) Sydnes, L. K.; Sandberg, M. Tetrahedron 1997, 53, 12679–12690.
(b) Sandberg, M.; Sydnes, L. K. Tetrahedron Lett. 1998, 39, 6361–6364.
(c) Sandberg, M.; Sydnes, L. K. Org. Lett. 2000, 2, 687–689. (d) Sydnes, L.
K.; Pedersen, G. S.; Holmelid, B.; Sanberg, M. Synthesis 2007, 3692–3696.
(e) Yadav, J. S.; Reddy, B. V. S.; Reddy, G. S. K. K. Tetrahedron Lett. 2000,
41, 2695–2697. (f) Kryshtal, G. V.; Bogdanov, V. S.; Yanovskaya, L. A.
Tetrahedron Lett. 1982, 23, 3607–3610.
(11) For other examples of intramolecular Friedel-Crafts acylations
employing catalytic levels of the Lewis acid, see: (a) Fillion, E.; Fishlock,
D.; Wilsily, A.; Goll, J. M. J. Org. Chem. 2005, 70, 1316–1327. (b) Fillion, E.;
Fishlock, D. Org. Lett. 2003, 5, 4653–4656. (c) Cui, D.-M.; Zhang, C.;
Kawamura, M.; Shimada, S. Tetrahedron Lett. 2004, 45, 1741–1745.
5738 J. Org. Chem. 2009, 74, 5738–5741
Published on Web 07/02/2009
DOI: 10.1021/jo900910b
r
2009 American Chemical Society

Womack et al.
JOCNote
acylals of cinnamaldehydes (3) also would undergo an
intramolecular Friedel-Crafts reaction to yield 2-alkyl-
1H-inden-1-yl acetates (4) and that saponification of 4 would
lead directly to 2. Of particular interest to us was the
potential of such a methodology for developing an industrial
synthesis of 2,6-dimethylindan-1-one (5), which can be used
to make 2,5-dimethyl-2-indanmethanol (6), a perfumery
compound with a powerful lily-of-the-valley, floral-type
odor.12 Previous approaches to 5 required either heating of
the requisite 3-arylcarboxylic acid in polyphosphoric acid13
or treatment of the corresponding acid chloride with 1 equiv
of AlCl3.14
TABLE 1. Preparation of 4a-ga
entry
R
enal (E/Z)
product
isolated yield (%)
1
2
3
4
5
6
7
Me
Et
100:0
96:4
96:4
60:40
95:5
92:8
91:9
4a
4b
4c
4d
4e
4f
36, 48b
79, 84b
78
Pr
iPr
Bu
82
83, 88c
84
pentyl
hexyl
4g
80, 82d
aReaction conditions: 1.5 equiv of Ac2O, 4 mol % FeCl3, rt, 1 day.
bReaction conditions: 3 equiv of Ac2O, 6 mol % FeCl3. cReaction
conditions: 2 h at rt. dReaction conditions: 3 equiv of Ac2O, 2 h at rt.
SCHEME 1. Mechanism for the Formation of 4
Both Pinnick et al.3 and Trost et al.7a,7b reported the
preparation of the diacetate acylal of (E)-cinnamaldehyde
by treatment of the enal with an excess of acetic acid
anhydride and a catalytic quantity of FeCl3 at 0 °C. We also
observed acylal formation when we treated cinnamaldehyde
with excess acetic anhydride and 4 mol % of FeCl3 at rt or
75 °C. GC-MS analysis showed no evidence for the forma-
tion of an indene product in either case. Polymerization to
higher molecular weight materials occurred in both reaction
mixtures, and after just a few hours at 75 °C, all of the enal
and acylal were consumed. However, when we treated
(E)-2-methylcinnamaldehyde with 1.5 equiv of acetic anhy-
dride and 4 mol % of FeCl3 at rt, the anticipated indenyl
acetate product (4a) was formed. GC analysis of the reaction
mixture after 3 h showed the presence of both 4a and the
acylal in about equivalent amounts. After 1 day of stirring,
4a was the major product and was isolated in 36% yield
(Table 1, entry 1). In contrast, the (E)-2-alkylcinnamalde-
hydes with larger alkyl groups reacted more efficiently to
form the indenyl acetates in yields of 78-84% with complete
consumption of the starting enals (entries 2-7). A 1-day
reaction period is not necessary because 4e was isolated
in 88% yield after a 2-h reaction period (entry 5). For
2-methylcinnamaldehyde, increasing the level of acetic an-
hydride to 3 equiv and the catalyst level to 6 mol % resulted
in the complete consumption of the enal and acylal but only
modestly improved the yield of 4a to 48% (entry 1).
the reaction conditions. The acid-catalyzed cyclization of
some 3-aryl-2-alkyl-2-propenals into 2-alkylindenols has
been reported but only in cases where the aryl ring bore
electron-donating groups.15 We found no evidence for in-
denol intermediates in our reaction mixtures, and no indene
products were observed in the absence of acetic anhydride. In
the case of 2-hexylcinnamaldehyde, treating the enal with
less catalyst (1 mol %) at 0 °C allowed the preparation of the
acylal (3g). However, even under these conditions, cycliza-
tion to 4g occurred, so the reaction mixture was worked up
after just 30 min to afford 3g in 59% yield (E/Z=85:15).
When a CH2Cl2 solution of 3g was treated with 4 mol %
FeCl3 at rt, the acylal was completely consumed within 1 h
and 4g was isolated in 87% yield.
On the basis of these results, we propose an intramolecular
Friedel-Crafts reaction in which an allylic oxocarbenium
ion, derived from the in situ generated acylal, alkylates the
phenyl group to form the indane skeleton (Scheme 1). This
process is analogous to that proposed for cyclization of the
dimethyl acetals of 2-alkylcinnamaldehydes.9,10 In order for
cyclization to occur, the stereochemical integrity of the enal
E-configured double bond must be lost. While this require-
ment was recognized previously in the case of acetal cycli-
zation, a pathway to account for it was not proposed.
A potential mechanism would be an allylic rearrangement
of the acylal to a 1,3-diacetoxy-1-propene intermediate
7 (Scheme 1). This intermediate could regenerate either the
Identification of the acylal in the 4a reaction mixture
indicated that indenyl acetates were formed by cyclization
of an initially formed acylal intermediate. However, another
possible pathway was that 2-alkylcinnamaldehydes cyclized
to indenol intermediates, which then were acetylated under
(12) (a) Vial, C.; Bernardinelli, G.; Schneider, P.; Aizenberg, M.; Winter,
€
B. Helv. Chim. Acta 2005, 88, 3109–3117. (b) Winter, B.; Gallo-Fluckiger, S.
Helv. Chim. Acta 2005, 88, 3118–3127.
(13) Fukuoka, M.; Yoshihira, K.; Natori, S.; Mihashi, K.; Nishi, M.
Chem. Pharm. Bull. 1983, 31, 3113–3128.
(14) Bachmann, W. E.; Cook, J. W.; Hewett, C. L.; Iball, J. J. Chem. Soc.
1936, 54–61.
(15) (a) Gupton, J. T.; Clough, S. C.; Miller, R. B.; Lukens, J. R.; Henry,
C. A.; Kanters, R. P. F.; Sikorski, J. A. Tetrahedron 2003, 59, 207–215.
(b) Singh, P. P.; Reddy, P. B.; Sawant, S. D.; Koul, S.; Taneja, S. C.; Kumar,
H. M. S. Tetrahedron Lett. 2006, 47, 7241–7243.
J. Org. Chem. Vol. 74, No. 15, 2009 5739

Womack et al.
JOCNote
SCHEME 2. Preparation of 2 and 8
TABLE 2. Indenyl Acetates with Substituents on the Aromatic Ringa
entry
aryl group
R
enal
product
isolated yield (%)
1
2
3
4
5
6
7
8
9
4-MeC6H4
2-MeC6H4
4-tBuC6H4
4-MeOC6H4
4-MeC6H4
2-MeC6H4
4-tBuC6H4
4-MeOC6H4
4-ClC6H4
Me
Me
Me
Me
Et
Et
Et
Et
Et
9a
9b
9c
9d
10a
10b
10c
10d
10e
11a
11b
11c
11d
12a
12b
12c
12d
12e
49
44
42
0b
82
82
89
25c
82
E- or Z-acylal, resulting in isomerization of the double bond,
or it could lead directly to the cationic species needed for the
intramolecular Friedel-Crafts reaction. While we did not
observe intermediate 7, the generation of 1,3-diacetoxy-
1-propenes from diacetate acylals of R,β-unsaturated alde-
hydes is known.16 These compounds also were noted as
minor byproducts in the FeCl3-catalyzed preparation of
the diacetate acylals of 2-hexenal and crotonaldehyde.7a
The only previously known member of the 4 series is 4a. It
was prepared in a five-step process involving conversion of
benzaldehyde to 2-methylindenone, NaBH4/CeCl3 reduc-
tion to 2-methyl-1-indenol (8a), followed by acetylation.17
Our new method for the direct conversion of 2-alkylcinna-
maldehydes to 4 is a much more convenient and direct route.
Convenient routes to 2-alkylindenols 8 and 2-alkylinda-
nones 2 were realized by the acid-catalyzed methanolysis or
saponification of 4, respectively (Scheme 2).
Indenols 8a-d were isolated in good yields after treating 4
with methanol and H2SO4 at rt. All proved to be solids, but
only 8a could be recrystallized. Base-catalyzed hydrolysis of
4 was expected to yield 2 via the initial formation of 8,
followed by double-bond migration to the enol. The base-
catalyzed conversion of indenols to indanones is known,18
and the migration of the indenyl double bond is believed to
proceed by a series of suprafacial 1,5-H shifts.19 Treatment
of 4g with methanolic NaOH (3 equiv) at rt resulted in the
complete consumption of indenyl acetate within 5 h and the
formation of two products. From this mixture, 8d and 2d
were isolated in 62% and 36% yields, respectively. Indanone
was obtained in 88% yield as the only product after heating
the reaction mixture at 60 °C for 1 day. Indanones 2a-c were
isolated in yields of 72-92% after being treated with 3 equiv
of NaOH at rt for 24 h.
aReaction conditions: 3 equiv of Ac2O, 4-6 mol % FeCl3, no solvent,
rt, 1 day (R = Me), 2-6 h (R = Et). bTrace level of 11d detected by GC-
MS analysis. cReaction conditions: 6 mol % FeCl3, rt, 8 h.
consumed within 2-8 h and resulted in indenyl acetate yields
of 82-89% (entries 5-7). A p-methoxy group on the aryl
ring resulted in significant decomposition and subsequently
low yields of the cyclized products (entries 4 and 8). In the
case of the 2-methylenal 9d, GC-MS analysis of the reaction
mixture indicated only a low level of the expected indenyl
acetate 11d and incomplete consumption of the starting enal
and acylal intermediate. Bulb-to-bulb distillation of this
reaction mixture showed that the experiment yielded mostly
a polymeric residue. Cyclization of the ethyl analogue 10d
was more efficient, but the catalyst level was increased to 6%
and the mixture stirred for 8 h to ensure consumption of the
starting enal. 12d was isolated in only 25% yield, with the
reaction producing mostly a polymeric residue. For 2-ethyl-
p-chlorocinnamaldehyde, the reaction proceeded normally
(6 mol % FeCl3 used) to yield 12e in 82% yield (entry 9).
Treatment of 11a with NaOH (rt, 1 day) yielded 5 in 81%
yield, the structure of which was confirmed by a comparison
with the literature NMR data for both 5 and 2,5-dimethyl-
indanone.13 The exclusive formation of 5 proves that cycli-
zation of the acylal proceeded without scrambling of the
acetate group between C(1) and C(3) of the resulting indene.
Because 11a was formed in only 49% yield, the overall
isolated yield of 5 from 9a was just 40%. Therefore, we
sought to improve the yield of the cyclization reaction. Other
Interested in a route to indanone 5, we prepared indenyl
acetates from 3-aryl-2-methylpropenals 9 and 3-aryl-2-ethyl-
propenals 10with substituentsonthe aromaticring(Table 2).
The enals were treated with 3 equiv of Ac2O and 4-6 mol %
FeCl3 at rt. As was found for the simple 2-alkylcinnamalde-
hydes (Table 1), the 2-methylenals 9 required a 1-day reac-
tion period to completely consume the starting enal and
afforded only moderate yields (42-49%) of indenyl acetates
(entries 1-3), while the corresponding 2-ethylenals 10 were
acids (SnCl4, BF3 Et2O, ZnCl2, AlCl3, EtAlCl2, TiCl4, and
3
H2SO4) were screened using our typical conditions (Table 2)
while monitoring the product yield by GC analysis with
dodecane as an internal standard. While SnCl4 and BF3
3
Et2O were comparable to FeCl3, none of the tested catalysts
proved superior. While we remained focused on FeCl3, other
reaction parameters were varied using the readily available
2-methylcinnamaldehyde as the substrate. Conditions were
developed that improved the isolated yield of 4a from 48%
(Table 1, entry 1) to 75% while reducing the catalyst level
from 6 mol % to just 0.5 mol %. This was achieved by
heating the enal/acetic anhydride (4 equiv) reaction mixture
at 116 °C for 30 min while adding the catalyst (0.5 mol %
(16) Smith, C. W.; Norton, D. G.; Ballard, S. A. J. Am. Chem. Soc. 1951,
73, 5282–5284.
(17) Pincock, J. A.; Young, I. S. Can. J. Chem. 2003, 81, 1083–1095.
(18) (a) Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.; Pridgen,
L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.; Baine, N. H. J. Am. Chem. Soc.
1998, 120, 4550–4551. (b) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y.
Tetrahedron Lett. 1999, 40, 4089–4092. (c) von Criegee, R. Justus Liebigs
Ann. Chem. 1930, 481, 263–302.
(19) (a) Friedrich, E. C.; Taggart, D. B. J. Org. Chem. 1975, 40, 720–723.
(b) Almy, J.; Hoffman, D. H.; Chu, K. C.; Cram, D. J. J. Am. Chem. Soc.
1973, 95, 1185–1190.
FeCl3 6H2O in 1 equiv of acetic anhydride) dropwise. Con-
version of 4a to 2a in 92% yield (Scheme 2) resulted in an
overall 69% yield of 2a from 2-methylcinnamaldehyde.
3
5740 J. Org. Chem. Vol. 74, No. 15, 2009

Womack et al.
JOCNote
Applying the same cyclization conditions to 9a improved the
yield of 11a from 49% to 68% for an overall yield of 55%
5 from the enal.
was mixed with 50 mL of methanol and 0.7 g (7 mmol) of
concentrated H2SO4. The mixture was stirred for 2 days at room
temperature and then neutralized with 1 g of Na2CO3. The
mixture was filtered and concentrated under vacuum. The
residue was subjected to bulb-to-bulb distillation or flash chro-
matography (95:5 hexane/ethyl acetate) to yield 8 as a pale-
yellow solid.
2-Methyl-1H-inden-1-ol (8a). From 3.0 g (16 mmol) of 4a,
1.7 g (11.6 mmol, 73% yield) of 8a was isolated by bulb-to-bulb
distillation (120 °C, 0.03 mmHg) as a pale-yellow solid. Recrys-
tallization from pentane/EtOAc afforded white crystals; mp=
83-85 °C (lit.17 mp 84-86 °C). NMR data matched that
reported in the literature:17 1H NMR (CDCl3, 400 MHz)
δ 2.00 (s, 3H), 2.10 (s, 1H), 4.72 (s, 1H), 6.27 (s, 1H), 7.04-
7.19 (m, 3H), 7.36 (d, J = 7.4 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 13.7 (q), 78.7 (d), 120.0 (d), 123.3 (d), 124.8 (d),
126.8 (d), 128.4 (d), 143.0 (s), 145.2 (s), 148.4 (s).
General Procedure for the Preparation of 2-Alkylindanones. In
a typical procedure, 20 mmol of indenyl acetate was mixed with
30 mL of MeOH and 20 mL of 3 M NaOH. In the case of 4a, 4d,
4e, and 9a, the mixtures were stirred at rt for 1 day. For 4g, the
reaction mixture was heated at 60 °C for 1 day. After neutraliza-
tion with 21 mL of 1.5 M H2SO4 and dilution with 100 mL of
water, the mixture was extracted with diethyl ether. The organic
phase was dried (MgSO4), filtered, and concentrated. The residue
was subjected to bulb-to-bulb distillation or flash chromatogra-
phy (98:2 hexane/ethyl acetate) to yield indanones 2 and 5.
2-Methylindanone (2a). A mixture of 4a (21.3 mmol), MeOH
(25 mL), and 3 M NaOH (22 mL) was stirred for 1 day and then
neutralized with 1.5 M H2SO4 (23.1 mL). After workup, bulb-
to-bulb distillation afforded 2.85 g (19.5 mmol, 92% yield) of 2a
as a pale-yellow oil. NMR data matched that reported in the
literature:21 1H NMR (CDCl3, 400 MHz) δ 1.31 (d, J=7.4 Hz,
3H), 2.66-2.74 (m, 2H), 3.39 (dd, J=8.2 and 17.4 Hz, 1H), 7.35
(t, J=7.4 Hz, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.57 (dt, J=7.5 and
1.1 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H)); 13C NMR (CDCl3,
100 MHz) δ 16.3 (q), 34.9 (t), 42.0 (d), 123.9 (d), 126.6 (d),
127.3 (d), 134.7 (d), 136.3 (s), 153.5 (s), 209.4 (s).
In conclusion, we have found that the in situ generated
acylals of 2-alkylcinnamaldehydes undergo an intramole-
cular Friedel-Crafts reaction to yield indenyl acetates at rt
in the presence of catalytic amounts of FeCl3 (4-6 mol %).
Yields from 2-methylcinnamaldehydes were moderate (36-
49%), while those from the corresponding 2-ethylcinnamal-
dehydes were good (82-89%). In the case of 2-methylcinna-
maldehyde, the yield of 4a was improved to 75% and
the catalyst level reduced to just 0.5 mol % by heating the
reaction mixture (116 °C) for 30 min while adding the
catalyst dropwise. Saponification of the indenyl acetates
afforded 2-alkylindanones in high yields. The net effect of
these two steps is acylation of the aryl ring using catalytic
quantities of the Lewis acid. In contrast, a traditional
Friedel-Crafts acylation route to 1-indanones requires at
least a stoichiometric level of the acid promoter.20
Experimental Section
General Procedure for the Preparation of Indenyl Acetates.
A mixture of 2-alkylcinnamaldehyde aldehyde (50 mmol) and
acetic anhydride (75-150 mmol) was cooled in an ice bath.
Anhydrous FeCl3 (0.3 g, 1.8 mmol) was added and the mixture
stirred for 15 min. The reaction mixture was removed from the
cold bath and stirred on the bench for 2-24 h. It was then
diluted with 100 mL of diethyl ether and washed with water (2 Â
50 mL). The organic phase was dried (MgSO4), filtered, and
concentrated. The products were isolated directly by bulb-to-
bulb distillation to yield acetates as pale-yellow liquids. In a few
cases, the distillates were further purified by flash chromatog-
raphy (hexane/EtOAc).
2-Methyl-1H-inden-1-yl Acetate (4a). A mixture of 2-methylcin-
namaldehyde (2.92 g, 20 mmol), acetic anhydride (6.1 g, 60 mmol),
and FeCl3 (0.2 g, 1.2 mmol) was stirred at rt for 1 day. After
workup, bulb-to-bulb distillation (140 °C, 0.025 mmHg) afforded
1.8 g (9.6 mmol, 48% yield) of 4a as a yellow oil. NMR data
matched that reported in the literature:17 1H NMR (CDCl3,
400 MHz) δ 1.97 (s, 3H), 2.17 (s, 3H), 6.14 (s, 1H), 6.41 (s, 1H),
7.07 (t, J=7.4 Hz, 1H), 7.11 (d, J=7.4 Hz, 1H), 7.22 (t, J=7.4 Hz,
1H), 7.35 (d, J = 7.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ 14.0 (q), 21.0 (q), 78.4 (d), 120.3 (d), 124.2 (d), 125.1 (d), 128.8 (d),
129.3 (d), 142.1 (s), 143.7 (s), 144.4 (s), 171.5 (s).
Acknowledgment. The authors are grateful to Dr. Estelle
Delort (Firmenich) and Erik Decorzant (Firmenich) for
measuring the high-resolution mass spectrometry data and
to Robert Brauchli (Firmenich) for assistance with NMR
measurements and interpretation.
Supporting Information Available: Details of the alternate,
reduced-catalyst experimental procedure for preparing 4a and
11a, procedure for preparing 3g, and compound characteri-
zation data and copies of the 1H and 13C NMR spectra for
compounds 2, 3g, 4, 8, 11, and 12. This material is available free
of charge via the Internet at http://pubs.acs.org.
General Procedure for the Preparation of 2-Alkylindenols. In a
typical procedure, 39 mmol of 2-alkyl-1H-inden-1-yl acetate
(20) For reviews on intramolecular acylation yielding 1-indanones, see:
(a) Heaney, H. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 2, pp 753-768. (b) Larock, R.
Comprehensive Organic Transformations, 2nd ed.; Wiley-VCH: New York,
1999; pp 1422-1433. (c) Popp, F. D.; McEwen, W. E. Chem. Rev. 1958, 58, 321–
401. (d) Johnson, W. S. Org. React. 1944, 2, 114–177.
(21) (a) Crich, D.; Yao, Q. J. Org. Chem. 1996, 61, 3566–3570.
(b) Boykin, D. W. J. Org. Chem. 1989, 54, 1418–1423.
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