Synthesis of substituted 4-aroyl-1-indanone and 5-aroyl-1-tetralone

Article abstract of DOI:10.1002/jccs.201190030

Several substituted 4-aroyl-1-indanones 2 and 5-aroyl-1-tetralones 3 were prepared in good yields from 1-indanones 1 via a series of reasonable transformations.

Full text of DOI:10.1002/jccs.201190030

306
Journal of the Chinese Chemical Society, 2011, 58, 306-308
Communication
Synthesis of Substituted 4-Aroyl-1-indanone and 5-Aroyl-1-tetralone
Meng-Yang Chang* and Nien-Chia Lee
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung 807, Taiwan, R.O.C.
Received January 18, 2011; Accepted April 6, 2011; Published Online April 11, 2011
Several substituted 4-aroyl-1-indanones 2 and 5-aroyl-1-tetralones 3 were prepared in good yields
from 1-indanones 1 via a series of reasonable transformations.
Keywords: Benzocycloalkanones; 4-Aroyl-1-indanone; 5-Aroyl-1-tetralone; Friedel-Crafts
acylation.
INTRODUCTION
RESULTS AND DISCUSSION
The bicyclic benzofused ring system, along with re-
lated structures such as indanone or tetralone, represents
the structural motifs of benzocycloalkanones.1 These cy-
clic systems incorporate two rings connected by a fused
ring containing a benzene ring adjacent to the ring junction.
This structural motif has been observed in a number of nat-
ural alkaloid products.2 The structural frameworks of 1-
indanones and 1-tetralones present a particular challenge
and their formation is the main focus of the research pre-
sented in this area.3 A number of unique approaches in re-
gard to 1-indanones and 1-tetralones have been explored
because it is an important intermediate for preparing natu-
ral products. Our interest is piqued by the synthesis of sub-
stituted 1-indanones and 1-tetralones with some different
potential biological properties;4 a facile method for the
regioselective synthesis of substituted 4-aroyl-1-indanones
2 and 5-aroyl-1-tetralones 3 from indanones 1 is described
in Scheme I.
Skeleton 1 was chosen as the starting materials for
synthesizing substituted 4-aroyl-1-indanones 2 and 5-aro-
yl-1-tetralones 3, as shown in Scheme II. Initially, skeleton
2 was provided by the Grignard addition of ketones 1a (R1
= H) and 1b (R1 = OMe) with arylmagnesium bromide (1.0
M in tetrahydrofuran, Ar = Ph, 4-FPh, 4-MeOPh) at rt for
4~5 h, followed by boron trifluoride etherate-mediated de-
Synthesis of 4-aroyl-1-indanones 2 and 5-
aroyl-1-tetralones 3
Scheme II
R1
1) ArMgBr, then BF -OEt
3
2) OsO , NMO then NaIO
2
4
4
Ar = Ph; 4-MeOPh; 4-FPh
O
1a, R = H
1
1b, R = OMe
1
R2
O
1
7
1) Ph P=CHOMe
3
2) Jones ox.
4
3) SOCl then AlCl
2
(for R = H, MeO)
3
1
2
Ar
O
R1
CHO
O
2a~2c, R = H
2
2d~2e, R = OH
2
Synthetic approach toward substituted
indanone
Scheme I
Ar
O
1) Ph P=CHCO Et
3
2) H , Pd/C
2
2
4
R
1
= H
R2
O
O
4a, Ar = Ph (38%)
4b, Ar = 4-MeOPh (31%) 3) 2N NaOH
4) POCl
R
= H, OMe; R = H, OH
2
1
5
4c, Ar = 4-FPh (20%)
= OMe
4d, Ar = Ph (49%)
3
3
Ar
O
( )
n
Ar = Ph, 4-FPh, 4-MeOPh
R1
(for R = H)
1
R
1
3a~3c
Ar
O
2, n = 1; 3, n = 2
1
4e, Ar = 4-MeOPh (40%)
* Corresponding author. Tel: +886-7-3121101 ext 2220; Fax: +886-7-3125339; E-mail: mychang@kmu.edu.tw

Synthesis of Substituted Aroyl Indanone and Tetralone
J. Chin. Chem. Soc., Vol. 58, No. 3, 2011 307
of various substituted 4-aroyl-1-indanones 2 and 5-aroyl-
1-tetralones 3 by photolytic induced methodology, in
search of useful compounds with potential biological activ-
ities.
Table 1. Synthesis of substituted 4-aroyl-1-indanones 2 and 5-
aroyl-1-tetralones 3a
Entry
2/3
R2 group
Ar group
Yield (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
3a
3b
3c
H
H
H
OH
OH
H
C6H5
4-CH3OC6H5
4-FC6H5
C6H5
4-CH3OC6H5
C6H5
81
55
62
70
61
73
59
68
In summary, we have successfully presented a conve-
nient synthetic methodology for producing a series of 4-
aroyl-1-indanones and 5-aroyl-1-tetralones. Further stud-
ies on the biological evaluation of the available compounds
are actively underway in laboratories.
H
H
4-CH3OC6H5
4-FC6H5
a The isolated products are > 95% pure as judged by 1H-NMR
analysis.
ACKNOWLEDGEMENTS
The authors would like to thank the National Science
Council of the Republic of China for its financial support
(NSC 99-2113-M-037-006-MY3). The project is also sup-
ported by a grant from the Kaohsiung Medical Research
Foundation (KMU-Q100004).
hydration of the resulting tertiary alcohol in dichloro-
methane at rt for 15~20 min. Without further purification,
osmium tetroxide-mediated dihydroxylation reaction of
the corresponding 1-arylindenes with N-methylmorpho-
line N-oxide in the co-solvent of t-butanol, tetrahydrofuran
and water (v/v/v = 1/3/6) afforded vicinal diols at reflux
temperature for 10~12 h, followed by sodium periodate-
mediated bond cleavage for 1~2 h to give skeleton 4. Com-
pounds 4a~4e were isolated in 20~49% total yields of four
steps.
REFERENCES
1. (a) Hong, B. C.; Sarshar, S. Org. Prep. Proced. Int. 1999, 31,
1. (b) 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. (c) Clark, W. M.;
Kassick, A. J.; Plotkin, M. A.; Eldridge, A. M.; Lantos, I.
Org. Lett. 1999, 1, 1839. (d) Minatti, A.; Zheng, X. L.;
Buchwald, S. L. J. Org. Chem. 2007, 72, 9253. (e) Arp, F. O.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482. (f) Kundu, K.;
McCullagh, J. V.; Morehead, A. T. J. Am. Chem. Soc. 2005,
127, 16042. (g) Itoh, T.; Mase, T.; Nishikata, T.; Iyama, T.;
Tachikawa, H.; Kobayashi, Y.; Yamamoto, Y.; Miyaura, N.
Tetrahedron 2006, 62, 9610. (h) Shintani, R.; Takatsu, K.;
Hayashi, T. Angew. Chem., Int. Ed. 2007, 46, 3735. (i)
Brekan, J. A.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem.
Soc. 2010, 132, 1472. (j) Coyanis, E. M.; Panayides, J.-L.;
Fernandes, M. A.; de Koning, C. B.; van Otterlo, W. A. L. J.
Orgmet. Chem. 2006, 691, 5222.
Furthermore, Wittig olefination of the skeleton 4,
subsequently followed by Jones oxidation, yielded keto-
acids. Finally, five compounds 2a~2e were isolated from
the ring-closure process via acylation of acids with thionyl
chloride and Friedel-Crafts reaction with aluminum chlo-
ride in 55~81% yields of four-steps.5-6 With the results in
hand, we envisioned that the demethylation should be in-
duced via the chelated aluminum intermediate between the
1-carbonyl and 7-methoxy group during the Friedel-Crafts
cyclization. To avoid demethylation, phorsphoryl trichlo-
ride was examined. When phorsphoryl trichloride-medi-
ated the intramolecular ring-closure step of the model keto-
acid (R1 = OMe, Ar = 4-FPh) substrate, compound 2f was
achieved with 79% yield (three-steps) without the forma-
tion of demethylated product. The structural frameworks of
compounds 2e and 2f were determined using single-crystal
X-ray analysis.7
2. For studies on the synthesis of members of this family of nat-
ural products, see: (a) Lomberget, T.; Bentz, E.; Bouyssi, D.;
Balme, G. Org. Lett. 2003, 5, 2055. (b) Banerjee, M.;
Makhopadhyay, R.; Achari, B.; Banerjee, A. Kr. Org. Lett.
2003, 5, 3931. (c) Ito, T.; Tanaka, T.; Iinuma, M.; Nakaya,
K.; Takahashi, Y.; Sawa, R.; Murata, J.; Darnaedi, D. J. Nat.
Prod. 2004, 67, 932. (d) Nagle, D. G.; Zhou, Y.-D.; Park, P.
U.; Paul, V. J.; Rajbhandari, I.; Duncan, C. J. G.; Pasco, D. S.
J. Nat. Prod. 2000, 63, 1431.
3. (a) Greene, A. E.; Coelho, F.; Barreiro, F. J.; Costa, P. R. R. J.
Org. Chem. 1986, 4250. (b) Corey, E. J.; Behforouz, M.;
Ishiguro, M. J. Am. Chem. Soc. 1979, 1608. (c) Girijia, T.;
Shanker, P. S.; Subba Rao, G. S. R. J. Chem. Soc., Perkin
Trans 1 1991, 1467. (d) Lauchli, R.; Schuler, G.; Boland, W.
Phytochemistry 2002, 61, 807.
According to the similar synthetic strategy of skele-
ton 2, skeleton 3 was also prepared from skeleton 4 via
Wittig olefination, hydrogenation, base-induced hydroly-
sis and followed sequentially by Friedel-Crafts acylation
with modest overall yields. The exhibited methodology
could provide a new and efficient route for the preparation
4. (a) Aono, T.; Kishimoto, S.; Araki, Y.; Noguchi, S. Chem.

308 J. Chin. Chem. Soc., Vol. 58, No. 3, 2011
Chang and Lee
Pharm Bull. 1978, 26, 1776. (b) Aono, T.; Araki, Y.; Tanaka,
K.; Imanishi, M.; Noguchi, S. Chem. Pharm Bull. 1978, 26,
1511. (c) Schuler, G.; Gorls, H.; Boland, W. Eur. J. Org.
Chem. 2001, 1663. (d) Zhang, Z.-P.; Krumm, T.; Baldwin, I.
T. J. Chem. Ecology 1997, 23, 2777. (e) Akritopoulou-
Zanze, I.; Albert, D. H.; Bousquet, P. F.; Cunha, G. A.; Har-
ris, C. M.; Moskey, M.; Dinges, J.; Stewart, K. D.; Sowin, T.
J. Bioorg. Med. Chem. Lett. 2007, 17, 3136.
26.95; Anal. Calcd for C16H12O3: C, 76.18; H, 4.79. Found:
C, 76.51; H, 4.98. For compound 2e: HRMS (ESI, M++1)
calcd for C17H15O4 283.0970, found 283.0972; 1H NMR (400
MHz): d 9.65 (br s, 1H), 7.77-7.73 (m, 3H), 6.99-6.95 (m,
2H), 6.82 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H), 3.39 (dt, J = 3.2,
5.6 Hz, 2H), 2.76 (dt, J = 3.2, 5.6 Hz, 2H); 13C NMR (100
MHz): d 210.47, 193.91, 163.28, 160.16, 157.76, 139.63,
132.06 (2x), 130.68, 127.45, 123.16, 113.75 (2x), 113.14,
55.51, 35.96, 26.58; Anal. Calcd for C17H14O4: C, 72.33; H,
5.00. Found: C, 72.65; H, 4.78. Single-crystal X-Ray dia-
gram: crystal of compound 2e was grown by slow diffusion
of ethyl acetate into a solution of compound 2e in dichloro-
methane to yield colorless prism. The compound crystallizes
in the monoclinic crystal system, space group P 1 21/c 1, a =
10.8910(19) Å, b = 11.973(2) Å, c = 10.0539(17) Å, V =
1310.0(4) Å3, Z = 4, dcalcd = 1.431 g/cm3, F(000) = 592, 2q
range 1.87~26.45o, R indices (all data) R1 = 0.0581, wR2 =
0.1540. For compound 3a: HRMS (ESI, M++1) calcd for
C17H15O2 251.1072, found 251.1077; 1H NMR (400 MHz): d
8.21 (dd, J = 1.6, 8.0 Hz, 1H), 7.82-7.78 (m, 2H), 7.61 (tt, J =
1.6, 8.0 Hz, 1H), 7.52-7.45 (m, 3H), 7.40 (t, J = 8.0 Hz, 1H),
2.92 (t, J = 6.0 Hz, 2H), 2.68 (dd, J = 6.0, 7.2 Hz, 2H), 2.11-
2.05 (m, 2H); 13C NMR (100 MHz): d 197.68, 197.49,
142.71, 138.65, 137.10, 133.64, 133.31, 132.84, 130.04
(2x), 129.31, 128.65 (2x), 126.01, 38.82, 27.37, 22.83; Anal.
Calcd for C17H14O2: C, 81.58; H, 5.64. Found: C, 81.90; H,
5.87. For compound 3b: HRMS (ESI, M++1) calcd for
C18H17O3 281.1178, found 281.1180; 1H NMR (400 MHz): d
8.17 (dd, J = 1.6, 7.6 Hz, 1H), 7.79-7.76 (m, 2H), 7.47 (dd, J
= 1.6, 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 6.95-6.92 (m,
2H), 3.87 (s, 3H), 2.88 (t, J = 6.4 Hz, 2H), 2.66 (t, J = 6.4 Hz,
2H), 2.09-2.03 (m, 2H); 13C NMR (100 MHz): d 197.74,
196.10, 164.05, 142.26, 139.19, 133.20, 132.44 (2x), 132.34,
129.94, 128.83, 125.98, 113.89 (2x), 55.52, 38.84, 27.24,
22.82. For compound 3c: HRMS (ESI, M++1) calcd for
C17H14FO2 269.0978, found 269.0981; 1H NMR (400 MHz):
d 8.19 (dd, J = 1.2, 7.6 Hz, 1H), 7.85-7.80 (m, 2H), 7.48 (dd,
J = 1.2, 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.17-7.11 (m,
2H), 2.90 (t, J = 6.0 Hz, 2H), 2.67 (t, J = 6.0 Hz, 2H),
2.10-2.04 (m, 2H); 13C NMR (100 MHz): d 197.51, 195.84,
167.29, 164.74, 142.58, 138.33, 133.36, 132.76, 132.66,
132.59, 129.37, 126.05, 115.97, 115.75, 38.77, 27.30, 22.77;
Anal. Calcd for C17H13FO2: C, 76.11; H, 4.88. Found: C,
76.29; H, 5.02.
5. For Friedel-Crafts acylation reaction, see: (a) Heaney, H. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 733. (b) Olah,
G. A. Friedel-Crafts Chemistry; John Wiley and Sons: New
York, 1973. For reviews on the intramolecular Friedel-Crafts
acylation reaction, see: (c) Heaney, H. In Comprehensive Or-
ganic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 2, p 753. (d) Sethna, S. In
Friedel–Crafts and Related Reactions; Olah, G. A., Eds.;
Interscience: New York, 1964; Vol. 3, p 911. (e) Gore, P. H.
Chem. Rev. 1955, 55, 229. (f) Johnson, W. S. Org. React.
1944, 2, 114.
6. For compound 2a: HRMS (ESI, M++1) calcd for C16H13O2
237.0916, found 237.0921; 1H NMR (400 MHz): d 7.95 (dd,
J = 0.4, 7.6 Hz, 1H), 7.81-7.77 (m, 3H), 7.63 (tt, J = 1.2, 6.8
Hz, 1H), 7.53-7.46 (m, 3H), 3.36-3.33 (m, 2H), 2.74-2.71
(m, 2H); 13C NMR (100 MHz): d 206.47, 196.16, 155.52,
138.28, 137.42, 135.78, 135.71 (2x), 133.13, 129.91 (2x),
128.58, 127.07, 126.82, 36.18, 25.83; Anal. Calcd for
C17H14O4: C, 72.33; H, 5.00. Found: C, 72.59; H, 5.23. For
compound 2b: HRMS (ESI, M++1) calcd for C17H15O3
267.1021, found 267.1024; 1H NMR (400 MHz): d 7.92 (dd,
J = 0.8, 7.6 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.74 (dd, J =
1.2, 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.8 Hz,
2H), 3.89 (s, 3H), 3.30-3.27 (m, 2H), 2.72-2.69 (m, 2H); 13C
NMR (100 MHz): d 206.56, 194.73, 163.78, 154.93, 138.10,
136.48, 134.99, 132.42 (2x), 129.93, 127.01, 126.23, 113.86
(2x), 55.54, 36.16, 25.49. For compound 2c: HRMS (ESI,
1
M++1) calcd for C16H12FO2 255.0821, found 255.0822; H
NMR (400 MHz): d 7.90 (dd, J = 0.8, 7.6 Hz, 1H), 7.83-7.78
(m, 2H), 7.72 (dd, J = 1.2, 7.6 Hz, 1H), 7.46 (dt, J = 0.8, 7.6
Hz, 1H), 7.18-7.12 (m, 2H), 3.31-3.28 (m, 2H), 2.70-2.67
(m, 2H); 13C NMR (100 MHz): d 206.22, 194.44, 166.92,
164.38, 155.29, 138.24, 135.34, 133.56, 132.54, 132.45,
127.04, 126.76, 115.83, 115.61, 36.04, 25.64; Anal. Calcd
for C16H11FO2: C, 75.58; H, 4.36. Found: C, 75.72; H, 4.63.
For compound 2d: HRMS (ESI, M++1) calcd for C16H13O3
7. CCDC 802675 (2e) and CCDC 805713 (2f) contain the sup-
plementary crystallographic data for this paper. This data
can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: 44-1223-336033; e-mail: de-
posit@ccdc.cam.ac.uk)
1
253.0865, found 253.0866; H NMR (400 MHz): d 9.73 (s,
1H), 7.78 (d, J = 8.4 Hz, 1H), 7.74-7.71 (m, 2H), 7.62-7.57
(m, 1H), 7.52-7.47 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 3.46-
3.43 (m, 2H), 2.79-2.76 (m, 2H); 13C NMR (100 MHz): d
210.50, 195.24, 160.60, 158.47, 140.36, 138.29, 132.40,
129.52 (2x), 128.46 (2x), 126.81, 123.26, 113.27, 35.97,