Microwave-assisted one-pot synthesis of 1-indanones from arenes and α,β-unsaturated acyl chlorides

Article abstract of DOI:10.1021/jo060022p

A series of 1-indanones were synthesized in good yields via tandem Friedel-Crafts acylation and Nazarov cyclization of arenes and α,β-unsaturated acyl chlorides in the presence of aluminum chloride under microwave irradiation.

Full text of DOI:10.1021/jo060022p

for superacidic trifluoromethanesulfonic acid-induced cyclia-
cyalkylation of arenes,5 competitive Friedel-Crafts alkylation
and/or acylation led to mixtures of 1-indanones, R,â-unsaturated
aromatic ketones, and 3-aryl carboxylic acids, with the latter
as major products in most cases.7 Furthermore, Friedel-Crafts
alkylation of 3-aryl R,â-unsaturated carboxylic acids affords 3,3-
diaryl carboxylic acids, which will produce different structural
isomers during the subsequent cyclization when the two aryl
groups are different. Because the acyl chloride predominantly
undergoes a Friedel-Crafts acylation rather than a Friedel-
Crafts alkylation, to avoid competitive intermolecular Friedel-
Crafts alkylation at the first step, active acyl chlorides should
be more suitable reactants instead of the corresponding acids.
However, although some 1-indanones could be prepared in good
yields by the reaction of substituted benzenes and R,â-
unsaturated acyl chloride under the catalysis of AlCl3 or
methanesulfonic acid, the substituted benzenes are limited to
benzene and electron-rich substituted benzenes.8
Microwave-Assisted One-Pot Synthesis of
1-Indanones from Arenes and r,â-Unsaturated
Acyl Chlorides
Wei Yin,† Yuan Ma,*,† Jiaxi Xu,‡ and Yufen Zhao†
Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology, Ministry of Education, Department of
Chemistry, Tsinghua UniVersity, Beijing 100084, People’s
Republic of China, and Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry and Molecular Engineering, Peking
UniVersity, Beijing 100871, People’s Republic of China
mayuan@mail.tsinghua.edu.cn
ReceiVed January 5, 2006
Microwave irradiation has been widely applied in organic
synthesis recently and achieved great success for many reac-
tions,9 including Friedel-Crafts acylations10 and Nazarov
cyclizations,11 with high efficiency and yields. Herein, we
present our results on the microwave-assisted one-pot synthesis
of 1-indanones from substituted benzenes and R,â-unsaturated
acyl chlorides in good yields.
First, we used identical conditions as reported by Koelsch et
al. with crotonic acid and benzene as starting materials.12
However, we failed to achieve the literature’s yield (81.5%; a
very low yield was obtained) in repeating the reaction several
times. Instead, crotonic acid was recovered in all cases. To
improve reactivity, we used more active crotonoyl chloride
instead of crotonic acid and obtained a mixture of 3-methyl-1-
A series of 1-indanones were synthesized in good yields via
tandem Friedel-Crafts acylation and Nazarov cyclization of
arenes and R,â-unsaturated acyl chlorides in the presence
of aluminum chloride under microwave irradiation.
1-Indanones are important synthetic intermediates for phar-
maceuticals and biologically active compounds1 and ligands of
olefin polymerization catalysts.2 There are numerous methods
available for the preparation of 1-indanones.3 The intramolecular
Friedel-Crafts acylation of 3-aryl carboxylic acids or the
corresponding acyl chlorides catalyzed by Lewis acids and/or
protic acids4 has been one of the oldest and most widely used
approaches because of its efficiency and convenience. The
educts were prepared generally from arenes and R,â-unsaturated
carboxylic acids. Actually, the intermolecular Friedel-Crafts
reaction of arenes and R,â-unsaturated carboxylic acids has also
been attempted to prepare 1-indanones.1d,5,6 However, except
(5) Surya Prakash, G. K.; Yan, P.; Toeroek, B.; Olah, G. A. Catal. Lett.
2003, 87, 109-112.
(6) Klumpp, D. A.; Rendy, R.; Zhang, Y.; Gomez, A.; McElrea, A. Org.
Lett. 2004, 6, 1789-1792.
(7) (a) Johnston, K. M.; Shotter, R. G. Tetrahedron 1974, 30, 4059-
4064. (b) Shotter, R. G.; Johnston, K. M.; Jones, J. F. Tetrahedron 1978,
34, 741-746.
(8) (a) Ready, T. E.; Chien, J. C. W.; Rausch, M. D. J. Organomet. Chem.
1999, 583, 11-27. (b) Ranu, B. C.; Jana, U. J. Org. Chem. 1999, 64, 6380-
6386. (c) Camps, F.; Coll, J.; Colomina, O.; Messeguer, A. Anorg. Chem.
Org. Chem. 1984, 39B, 1801-1805. (d) Boberg, F.; Deters, K.; Schulz, J.;
Torges, K. Phosphorus, Sulfur Silicon Relat. Elem. 1994, 91, 69-80. (e)
Jefferson, A.; Wangchareontrakul, S. Aust. J. Chem. 1985, 38, 605-614.
(f) Bhattacharyya, S.; Basu, B.; Mukherjee, D. Tetrahedron 1983, 39, 4221-
4224. (g) Dupin, J. F. E.; Chenault, J. Heterocycles 1983, 20, 2401-2404.
(h) Miyamoto, T. K.; Tsutsui, M.; Chen, L. Chem. Lett. 1981, 729-730.
(i) Conover, L. H. J. Am. Chem. Soc. 1953, 75, 4017-1020. (j) Colonge,
J.; Daunis, H. Bull. Soc. Chim. Fr. 1961, 2238-2241. (k) Granger, I.;
Corbier, M.; Vinas, J.; Nau, P. Bull. Soc. Chim. Fr. 1957, 810-814. (l)
Knorr, I.; Lattke, E.; Raepple, E. Liebigs Ann. Chem. 1980, 1207-1215.
(9) For recent reviews, see: (a) Kappe, C. O.; Stadler, A. In MicrowaVes
in Organic and medicinal Chemistry; from the series, Methods and
principles in Medicinal Chemistry; Mannhold, R., Kubinyi, H., Folker, G.,
Eds.; Wiley-VCH: Weinheim, 2005; Vol. 25. (b) Hayes, B. L. Aldrichimica
Acta 2004, 37, 66-77. (c) Loupy, A., Ed. MicrowaVes in Organic Synthesis;
Wiley-VCH: Weinheim, 2002. For recent examples, see: (d) Liang, Y.;
Jiao, L.; Zhang, S. W.; Xu, J. X. J. Org. Chem. 2005, 70, 334-337. (e)
Wetter, C.; Studer, A. Chem. Commun. 2004, 174-175.
* To whom correspondence should be addressed. Phone: +86-10-62792673.
Fax: +86-10-62792673.
† Tsinghua University.
‡ Peking University.
(1) For examples, see: (a) Bogeso, K. P.; Christensen, A. V.; Hyttel, J.;
Liljefors, T. J. Med. Chem. 1985, 28, 1817-1828. (b) Bogeso, K. P.; Arnt,
J.; Frederiksen, K.; Hansen, H. O.; Hyttel, J.; Pedersen, H. J. Med. Chem.
1995, 38, 4380-4392. (c) Sugimoto, H. Pure Appl. Chem. 1999, 71, 2031-
2037. (d) Guillon, J.; Dallemagne, P.; Leger, J.-M.; Sopkova, J.; Bovy, P.
R.; Jarry, C.; Rault, S. Bioorg. Med. Chem. 2002, 10, 1043-1050.
(2) For examples, see: (a) Schumann, H.; Stenzel, O.; Girgsdies, F.
Organometallics 2001, 20, 1743-1751. (b) Herzog, M. N.; Chien, J. C.
W.; Rausch, M. D. J. Organomet. Chem. 2002, 654, 29-35.
(3) For a recent summary, see: Wessig, P.; Glombitza, C.; Muller, G.;
Teubner, J. J. Org. Chem. 2004, 69, 7582-7591.
(4) For recent examples, see: (a) Premasagar, V.; Palaniswamy, V. A.;
Eisenbraun, E. J. J. Org. Chem. 1981, 46, 2974-2976 and references therein.
(b) Cui, D. M.; Zhang, C.; Kawamura, M.; Shimada, S. Tetrahedron Lett.
2004, 45, 1741-1745. (c) Rendy, R.; Zhang, Y.; McElrea, A.; Gomez, A.;
Klumpp, D. A. J. Org. Chem. 2004, 69, 2340-2347.
(10) Paul, S.; Nanda, P.; Gupta, R.; Loupy, A. Synthesis 2003, 2877-
2881 and references therein.
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S.; McGown, A. T. Tetrahedron Lett. 2006, 47, 1637-1640.
(12) Koelsch, C. F.; Hochmann, H.; Le Claire, C. D. J. Am. Chem. Soc.
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10.1021/jo060022p CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/02/2006
4312
J. Org. Chem. 2006, 71, 4312-4315

TABLE 1. Reaction of Benzene and Crotonoyl Chloride
1c-e expectedly provided both structural isomers 4 and 5. Most
of them could be chromatographically separated and character-
ized via 1H NMR. The 3,5-disubstituted isomers 4 were isolated
as the major products, clearly indicating that the initial Friedel-
Crafts acylation occurred predominantly para to the substituent.
Biphenyl 1f provided the 3,5-isomer 4f exclusively. Toluene
1b provided both isomers 4b and 5b. Interestingly, with the
higher alkyl benzene homologues ethyl benzene (not shown),
isopropyl benzene (1g), and tert-butyl benzene (1h), an increas-
ing rate of concomitant dealkylation was observed. Conse-
quently, ethyl benzene provided a mixture of the 5- and
7-isomers accompanied by 4a. 1g reacted to form a mixture of
4g and 4a, whereas 1h suffered from complete dealkylation
providing 4a in 78% yield (entries 7 and 8, Table 2).
reaction
yield of yield of
entry
solvent
PhH
conditions
reaction time
5 h
5 h
5 h
5 h
16 h
18 h
3 (%)
4a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
reflux
reflux
reflux
80 °C
80 °C
80 °C
55
42
trace
CS2
PhNO2
PhNO2
PhNO2
PhNO2
PhNO2
PhNO2
3
11
12
10
22
22
41
36
58
77
79
rt + 80 °Ca 5 h + 18 h
rt + 80 °C 24 h + 18 h
Second, 1a and halobenzenes 1c-e were reacted with
cinnamoyl chloride 2b under optimized conditions providing
mixtures of the 5- and 7-isomers of the desired 1-indanones in
yields of 72-97%.
o-C6H4Cl2 rt + 80 °C 5 h + 18 h
o-C6H4Cl2 MWb
3 × 1.5 min
o-C6H4Cl2 MWb
5 × 5 min
o-C6H4Cl2 rt + MWb
5 h + 5 × 5 min
5 h + 10 × 2 min
o-C6H4Cl2 rt + MWb
When reacting the less-reactive halobenzenes with 2a or 2b,
small amounts of dichloro-1-indanones were detected via mass
spectroscopy, indicating that the solvent participated in the
reaction. We evaluated the reactivity of the solvent by reacting
o-dichlorobenzene with 2a and provided actually only two of
three possible isomers. 5,6-Dichloro-3-methyl-1-indanone (4k)
and 4,5-dichloro-3-methyl-1-indanone (4k′) were obtained in
yields of 20% and 29%, respectively, and were identified by
a Stirred at rt for 5 h and then at 80 °C for 18 h. b Irradiated under
microwave at 185 °C at intervals. It takes about 30 s to achieve 185 °C
under microwave conditions.
indanone, 1-phenyl-but-2-en-1-one, and 1,3-diphenyl-1-butanone
(23% yield, not shown in Table 1) (entry 1, Table 1). To
suppress the Friedel-Crafts alkylation of 1-phenyl-but-2-en-1-
one and benzene, we decreased the amount of benzene to
equimolar amount of acyl chloride. The one-pot reaction of
crotonoyl chloride and benzene was selected as a model reaction
to optimize the reaction conditions. The results are summarized
in Table 1. 1-Phenyl-2-buten-1-one was obtained as a major
product under refluxing in carbon disulfide as solvent. To
improve the reaction temperature, nitrobenzene was used as
solvent. Under refluxing conditions, the reaction mixture
darkened, but no desired product was found. Lowering the
reaction temperature to 80 °C provided the desired 3-methyl-
1-indanone (4a), albeit in low yields. The yield of 4a was
improved when the solution of crotonoyl chloride and benzene
in nitrobenzene was stirred at room temperature for 5 h and
then heated at 80 °C for 18 h. A longer reaction time at room
temperature of 24 h did not improve yields (entries 7 and 8,
Table 1). Under the same conditions, but using o-dichloroben-
zene as solvent, the yield of 4a was remarkably increased (entry
9, Table 1). The yield was further improved when the reaction
mixture was irradiated in a microwave field for 5 × 5 min (entry
11, Table 1). Finally, an optimized yield of 79% was achieved
under microwave irradiation (10 × 2 min) at intervals. Pulsed
microwave irradiation gave higher yields than irradiating the
reaction mixture continuously for the same period of time. This
phenomenon has also been discovered by other investigators,
although the reason is not stated.13 In our case, the continuous
irradiation overheated the reaction mixture and caused black
tarlike products. In recent years, an alternative method for
performing microwave-assisted organic reactions, termed “en-
hanced microwave synthesis” (EMS), has been examined.9b In
this method, microwave irradiation is administered while
simultaneously externally cooling the reaction vessel with
compressed air. It enables a greater amount of microwave energy
to be introduced into a reaction while keeping the reaction
temperature low.14 This may offer an alternative operation to
the pulsed approach.
1
their H NMR spectra and NOE experiments (see Supporting
Information). Both of them were formed from para acylation
of o-dichlorobenzene and subsequent cyclization. Although
o-dichlorobenzene can react with crotonoyl chloride and cin-
namoyl chloride, it does not affect the desired reaction in most
cases because of its lower reactivity.
The reaction process proceeds as follows: first, Friedel-
Crafts acylation between a substituted benzene and an R,â-
unsaturated acyl chloride occurs (stirring the reaction mixture
at room temperature favors this process), and then an aromatic
Nazarov cyclization gives rise to a 1-indanone. Although the
cyclization of aryl vinyl ketones generally is considered a
Nazarov cyclization15 and it is generally considered that an
aromatic ketone hardly undergoes a Friedel-Crafts alkylation,
the Friedel-Crafts alkylation of 1-phenyl-but-2-en-1-one and
benzene was observed (Table 1, entry 1). In the current case,
the formed ketone 3 generally exists favorably in the s-cis
conformation. Its AlCl3-coordinated complex 6 should predomi-
nately convert to the s-trans conformation 7 because of the
increasing size of the oxygen group. The carbon atom of the
AlCl3-coordinated carbonyl group could act as a carbocation
as suggested in a recent report,16 which could induce a CdC
bond rearrangement to form an allylic or an allylic and benzylic
carbocation 8. The enolic carbocation 8 could easily undergo
an intramolecular Friedel-Crafts alkylation to yield an indene-
type intermediate 9, which gives rise to the desired 1-indanone
(13) Baxendale, I. R.; Lee, A.-L.; Ley, S. V. J. Chem. Soc., Perkin Trans.
1 2002, 1850-1857.
(14) (a) Chen, J. J.; Deshpande, S. V. Tetrahedron Lett. 2003, 44, 8873-
8876. (b) Humphrey, C. E.; Easson, M. A. M.; Tierney, J. P.; Turner, N. J.
Org. Lett. 2003, 5, 849-852. (c) Katritzky, A. R.; Zhang, Y.; Singh, S. K.;
Steel, P. J. ArkiVoc. 2003, 47-64.
(15) For recent reviews, see: (a) Habermas, K. L.; Denmark, S. E.; Jones,
T. K. Org. React. 1994, 45, 1-158. (b) Pellissier, H. Tetrahedron 2005,
61, 6479-6517. (c) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61,
7577-7606.
(16) Xu, J. X.; Xia, J. K.; Lan, Y. Synth. Commun. 2005, 35, 2347-
2353.
After successful optimization, we expanded the scope of the
reaction to various substituted benzenes (Table 2). Halobenzenes
J. Org. Chem, Vol. 71, No. 11, 2006 4313

TABLE 2. Synthesis of 1-Indanones from Arenes and r,â-Unsaturated Acyl Chloridesa
4314 J. Org. Chem., Vol. 71, No. 11, 2006

Table 2 (Continued)
a Stirred at rt for 5 h and then irradiated under microwave at 185 °C for 10 × 2 min at intervals. It takes about 30 s to achieve 185 °C under microwave
conditions. b Total yield of the mixture of 4 and 5. c Isolated yields after column chromatography. d Measured by 1H NMR of the crude products. e Measured
by HPLC analysis of the crude products on a ZORBAX Sil column (4.6 × 150 mm) with a mixture of hexane and 2-propanol (98:2, v/v) as eluent monitored
at 254 nm.
SCHEME 1. Proposed Reaction Mechanism (Electrophilic
Attack at Para Position Shown)
microwave conditions. Between the two irradiations, the reaction
temperature was allowed to cool to about 60 °C. After hydrolysis
by addition of concentrated hydrochloric acid (15 mL) and ice, the
resulting mixture was extracted with diethyl ether (3 × 25 mL).
The combined organic phase was washed by 2 mol/L HCl (30 mL)
twice, water, saturated sodium bicarbonate, and water and dried
over anhydrous sodium sulfate. After removal of solvent, the residue
was separated on a silica gel column with a mixture of petroleum
ether (60-90 °C) and ethyl acetate (40:1 to 25:1, v/v) as eluent to
afford the desired 1-indanone as product. To obtain pure product,
most products were purified twice on the silica gel column.
5-Bromo-3-phenyl-1-indanone (4o). Colorless crystals. Mp 98-
100 °C. Rf ) 0.25 [ethyl acetate/ petroleum ether (60-90 °C) 1:15,
v/v, silica gel plate]. IR (KBr) V (cm-1): 1713.4 (CdO). 1H NMR
(300 MHz, CDCl3): δ 7.84-6.93 (m, 8H), 4.58 (dd, J ) 8.2, 3.8
Hz, 1H), 3.23 (dd, J ) 19.1, 8.2 Hz, 1H), 2.62 (dd, J ) 19.1, 3.8
Hz, 1H). 13C NMR (75.5 MHz, CDCl3): δ 43.6, 46.4, 123.7, 126.7,
127.0, 128.3, 129.6, 130.9, 135.3, 136.7, 143.9, 156.5, 204.8. MS
(EI) m/z (rel intensity, %): 286 (M+, 84), 207 (M+ - Br, 97), 77
(100). HRMS cacld for C15H11BrO (M+), 285.9993; found,
285.9985.
7-Bromo-3-phenyl-1-indanone (5o). Colorless crystals. Mp 68-
70 °C. Rf ) 0.38 [ethyl acetate/ petroleum ether (60-90 °C) 1:15,
v/v, silica gel plate]. IR (KBr) V (cm-1): 1713.4 (CdO). 1H NMR
(300 MHz, CDCl3): δ 7.83-7.11 (m, 8H), 4.58 (dd, J ) 7.9, 3.7
Hz, 1H), 3.23 (dd, J ) 19.3, 7.9 Hz, 1H), 2.69 (dd, J ) 19.3, 3.7
Hz, 1H). 13C NMR (50 MHz, CDCl3): δ 44.4, 46.8, 123.4, 126.8,
126.9, 127.6, 127.8, 128.9, 135.0, 136.7, 143.6, 157.9, 205.9. MS
(EI) m/z (rel intensity, %): 286 (M+, 7), 208 (M+ - PhH, 100),
207 (M+ - Br, 27), 193 (12), 179 (38), 165 (27), 77 (18). HRMS
cacld for C15H11BrO (M+), 285.9993; found, 285.9985.
after hydrolysis and tautomerization (Scheme 1). It is impossible
to distinguish whether the cyclization is an aromatic Nazarov
cyclization or an intramolecular Friedel-Crafts alkylation. We
considered it as a dual process.
In conclusion, a series of 1-indanones were synthesized in
good yields via the tandem Friedel-Crafts acylation and
Nazarov cyclization of substituted benzenes and R,â-unsaturated
acyl chlorides in the presence of aluminum chloride under
microwave irradiation. The current route is a practical and
convenient method for the synthesis of 1-indanone derivatives
from simple starting materials in a one-pot reaction, albeit it
shows low regioselectivity for toluene and halobenzene.
Acknowledgment. This work was supported in part by
Experimental Section
Tsinghua University.
General Procedure for the Preparation of 1-Indanones. A
dried round-bottom flask (50 mL) equipped with a condenser capped
with an anhydrous CaCl2 drying tube was charged with a solution
of arene 1 (3 mmol), R,â-unsaturated acyl chloride (3.3 mmol),
and anhydrous aluminum chloride (9 mmol) in 6 mL of dried
o-dichlorobenzene. The solution was stirred at room temperature
for 5 h and then irradiated under microwave at 185 °C for 10 × 2
min at intervals. It takes about 30 s to achieve 185 °C under
Supporting Information Available: The experimental details,
1
the analytical data of products 4 and 5, H NMR and 13C NMR
spectra for the unknown 1-indanones 4g, 4k, 4k′, 4m, 4o, 5c-e,
and 5o, and the 1H NMR NOE spectrum for the unknown
1-indanone 4k′. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO060022P
J. Org. Chem, Vol. 71, No. 11, 2006 4315