A Convenient Synthesis of 7-Halo-1-indanones and 8-Halo-1-tetralones

Article abstract of DOI:10.1021/jo035289s

A regioselective oxidation of N-indan-4-yl-acetamide or N-(5,6,7,8-tetrahydronaphthalen-1-yl)acetamide with potassium permanganate followed by acidic hydrolysis gave 7-aminoindan-1-one or 8-aminotetral-1-one in good yield. The amino ketones were converted to the corresponding 7-haloindanone or the 8-halotetralone. Another method to prepare 7-haloindan-1-ones was completed by a cyclization of 3-chloro-1-(2-halophenyl)propan-1-one under Friedel-Crafts conditions to produce the product in gram quantity.

Full text of DOI:10.1021/jo035289s

A Con ven ien t Syn th esis of
7-Ha lo-1-in d a n on es a n d 8-Ha lo-1-tetr a lon es
Phong Nguyen, Evelyn Corpuz, Todd M. Heidelbaugh,*
Ken Chow, and Michael E. Garst
Allergan, Inc., 2525 Dupont Drive, Irvine, California 92623
heidelbaugh_todd@allergan.com
F IGURE 1. 7-Haloindanone and 8-halotetralone.
Received September 2, 2003
literature.6 For example, the cyclization of 3-(3-acetyl-
aminophenyl)propionyl chloride with AlCl3 gives pre-
dominately the 5-acetomido-1-indanone in a 40:1 ratio
with the 7-substituted compound 13.7 Cyclization of 3-(3-
bromophenyl)propionyl chloride under Friedel-Crafts
conditions gave a 4.4:1 mixture of the 5-bromo- vs
7-bromoindanone (3).4 A blocking/deblocking strategy is
required to enforce the proper regiochemical outcome
under these conditions. This protection/deprotection
scheme requires at least 8 steps and is of moderate
yield.3,4a Alternatively, one could employ a metalation
tactic. The directed ortho-metalation5 can be technically
challenging on a preparative scale and purification of the
product can be problematic. These difficulties are pro-
nounced in the preparation of the fluorinated compounds.
Another method that has been used is the acid-catalyzed
cyclization of 1-(2-chlorophenyl)propenone in concen-
trated H2SO4. This reaction yields the 7-chloroindanone
in a modest yield (14%).2 The difficulties of these methods
have limited the use of these desirable materials in
structure-activity relationship studies and synthetic
chemistry in general.
Abstr a ct: A regioselective oxidation of N-indan-4-yl-aceta-
mide or N-(5,6,7,8-tetrahydronaphthalen-1-yl)acetamide with
potassium permanganate followed by acidic hydrolysis gave
7-aminoindan-1-one or 8-aminotetral-1-one in good yield.
The amino ketones were converted to the corresponding
7-haloindanone or the 8-halotetralone. Another method to
prepare 7-haloindan-1-ones was completed by a cyclization
of 3-chloro-1-(2-halophenyl)propan-1-one under Friedel-
Crafts conditions to produce the product in gram quantity.
The efficient preparation of functionalized cyclic struc-
tures is important in the search for bioactive small
molecules. In the course of an ongoing project, we desired
to synthesize indans and tetralins with substitution at
the 7- or 8-position, respectively. In particular, we sought
a concise, flexible method to produce 7-haloindanones and
8-halotetralones without the need for challenging condi-
tions or difficult purifications. We wanted to include the
fluoro group in our study due to its interesting properties
and prominent use in pharmaceuticals and agrochemi-
cals.1 In this paper we report a general, divergent method
for the convenient preparation of the entire family of
7-haloindanones and 8-halotetralones, and a linear 3-step
synthesis of 7-haloindanones.
We were surprised to find no efficient method to
prepare these particular compounds (Figure 1) and the
preparation of most of these compounds has not been
reported to date. The literature contains a few procedures
for the preparation of the 7-chloroindanone (2)2,3 and
7-bromoindanone (3)4 but no accounts could be found for
the preparation of the fluoro (1) or iodo (4) analogues.
As for the 8-halotetralones, we found only the chloro
analogue in the literature.5 The known procedures for
the preparation of these compounds are lengthy, not
general, and relatively low yield. Published methods for
the preparation of this family of compounds are sum-
marized below. The classical cyclization with the Fre-
idel-Crafts reaction gives the undesired 5-substituted
product due to several factors as discussed in the
We directed our effort to find a common intermediate
that could be used to generate any of the halogenated
target compounds. Our preparation of this family of
compounds took the following route. Indan-4-ylamine (9)
was converted to N-indan-4-yl-acetamide (11) with acetic
anhydride, which proved to be superior to the use of
acetyl chloride/NEt3.8 The regioselective oxidation9,10 of
11 with KMnO4 in acetone/H2O in the presence of MgSO4
gives N-(3-oxo-indan-4-yl)acetamide (13) in 75% yield.
1
None of the 4-amidoindanone was observed by H NMR.
This control is very useful and compliments the analo-
gous oxidation of 4-nitroindan that produces 4-nitroin-
dan-1-one as the major product.11 This transformation
was found to be very similar to the method for the
oxidation of N-(5,6,7,8-tetrahydro-1-naphthyl)acetamide
12 as described in the literature.9 Acidic hydrolysis of 13
(6) Kenner, J .; Witham, E. J . Chem. Soc. 1921, 119, 1452.
(7) Biggs, D. F.; Casy, A. F.; Chu, I.; Coutts, R. T. J . Med. Chem.
1976, 4, 472.
* Corresponding author.
(8) Morita, S.; Otsubo, K.; Matsubara, J .; Ohtani, T.; Uchida, M.
Tetrahedron: Asymmetry 1995, 6, 245.
(1) Tagat, J . R.; McCombie, S. W.; Nazareno, D. V.; Boyle, C. D.;
Kozlowski, J . A.; Chackalamannil, S.; J osien, H.; Wang, Y.; Zhou, G.
J . Org. Chem. 2002, 67, 1171.
(2) (a) Deady, L. W.; Desneves, J .; Kaye, A. J .; Thompson, M.; Finlay,
G. J .; Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 1999, 7, 2801.
(b) Thorsett, E. D.; Stermitz, F. R. Synth. Commun. 1972, 2, 375.
(3) Feiser, L. F.; Berliner, E. J . Am. Chem. Soc. 1952, 74, 536.
(4) (a) GB 1249375, 1971. (b) Babin, D.; Demoute, J .-P. WO 8908096,
1989.
(9) (a) Sugimori, M.; Ejima, A.; Ohsuki, S.; Uoto, K.; Mitsui, I.;
Matsumoto, K.; Kawato, Y.; Yasuoka, M.; Sato, K.; Tagawa, H.;
Terasawa, H. J . Med. Chem. 1994, 37, 3033. (b) Sugimori, M.; Ejima,
A.; Ohsuki, S.; Uoto, K.; Mitsui, I.; Kawato, Y.; Hirota, Y.; Sato, K.;
Terasawa, H. J . Med. Chem. 1998, 2, 375. (c) Olson, R. E.; Maduskuie,
T. P.; Thompson, L. A.; Tebben, A. J .; Wang, N.; Deng, W.; Liu, H.
WO 01/60826 A2.
(10) Shaabani, A.; Bazgir, A.; Teimouri, F.; Lee, D. G. Tetrahedron
Lett. 2002, 43, 5165.
(11) Hahn, R. C.; Howard, P. H.; Lorenzo, G. A. J . Am. Chem. Soc.
1971, 93, 5816.
(5) (a) Godel, T.; Gutknecht, E.-M. EP 0 606 661 B1, 1994. (b)
Sneikus, V. Chem. Rev. 1990, 90, 879. (c) Panetta, C. A.; Dixit, A. S.
Synthesis 1981, 59.
10.1021/jo035289s CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/03/2003
J . Org. Chem. 2003, 68, 10195-10198
10195

lobenzoic acid (17-19) was followed by cyclization to the
indanone product. The cyclization method with Freidel-
Crafts conditions of 1-(2-halo-phenyl)-3-chloro-propan-1-
one (20-22) is particularly useful in the preparation of
gram quantities of haloindanones (1-3). It should be
noted that this method is not applicable to formation of
the tetralone system because the reaction of 1-(2-
halophenyl)-4-chlorobutan-1-one readily forms the more
favored 3-methylindanone.14
In regard of Figure 2, the successful preparation of the
fluoro compounds 1 and 5 compared favorably with
previously reported yields for fluorinations of this type.
The limitation in yield (30-40%) of this particular
Schiemann reaction is due to the presence and position
of the carbonyl group as documented in the literature.16
Conversion of the amines to the 7- or 8-chloro compounds
2 (64%) or 6 (78%) was accomplished in good yield with
tBuONO and CuCl2. During bromination, use of the
method with tBuONO and CuBr2 gave a 2:1 mixture of
4,7-dibromoindan-1-one and the desired compound 3.
Conversion of the 7- or 8-amino compound to the 7- or
8-bromo compound was accomplished with a Sandmeyer-
type reaction, using NaNO2, HBr, and CuBr: 3 (60%
yield) and 7 (70% yield).17 This method was also used to
form the iodo compounds 4 (43%) and 8 (60%).
F IGURE 2. Summary of methods and yields.
SCHEME 1. A gen er a l a n d d iver gen t
r egioselective oxid a tion m eth od
In conclusion, the facile preparation of 7-substituted
indanones and 8-substituted tetralones is of interest to
synthetic and medicinal chemists. This observation is
illustrated by the variety of synthetic approaches ap-
pearing in several papers2,3,6 and patents.4,5a In this
paper, we have reported the regioselective oxidation of
7-amidoindans as applied to the preparation of 7-haloin-
danone. Also, we have included practical laboratory
preparations of the 7-haloindanones and 8-halotetral-
ones. We can now add these high-value intermediates to
the synthetic chemist’s toolbox.
SCHEME 2. A cycliza tion m eth od for a lin ea r
syn th esis of 7-h a loin d a n on es
Exp er im en ta l Section
P r ep a r a tion of 7-Am in oin d a n -1-on e (15): N-In d a n -4-yl-
a ceta m id e (11). Indan-4-ylamine (9; 13.5 g, 101 mmol) in EtOH
(55 mL, anhydrous) was added to acetic anhydride (19 mL, 201
mmol) in EtOH (300 mL) at 0 °C.8 The mixture was stirred for
16 h at room temperature. The solvent was removed under
vacuum on a rotary evaporator to yield N-indan-4-yl-acetamide
(11) as a white solid (∼17 g) that was used without further
purification. 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J ) 8.0 Hz,
1H), 7.26 (br s, 1H), 7.12 (t, J ) 7.5 Hz, 1H), 7.01 (d, J ) 7.5 Hz,
1H), 2.93 (t, J ) 8.0 Hz, 2H), 2.79 (t, J ) 7.5 Hz, 2H), 2.16 (s,
3H), 2.10-2.04 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 168.6,
145.5, 134.8, 134.1, 127.3, 121.1, 119.6, 33.4, 30.4, 25.0, 24.5;
HRMS m/z calcd for C11H13NO 175.0997, obsd 175.1006.
N-(3-Oxo-in d a n -4-yl)a ceta m id e (13). N-Indan-4-yl-aceta-
mide (11; ∼17 g, 97 mmol) in acetone (600 mL) and 15% aqueous
MgSO4 (16 g in 90 mL of H2O) at room temperature was treated
with KMnO4 (46 g, 228 mmol). The mixture was allowed to stir
at room temperature for 16 h. The mixture was filtered through
Celite and the solids were washed with CHCl3 and water. The
gave 7-aminoindanone (15) in good yield. Amine 15 was
employed in the synthesis12,13 of the 7-haloindanones 1-4
(Figure 2). The same route that produced the amino
indanone (15) was used for the preparation of aminote-
tralone (16).9 The 8-halotetralones 5-8 were also pre-
pared in a similar fashion (see Figure 2).
A complimentary route to efficiently synthesize 7-ha-
loindanones (Scheme 2) was adapted from a method for
the synthesis of 1-indanones.14,15 Homologation of 2-ha-
(16) (a) Roe, A. Org. React. 1949, 5, 193. (b) Zenitz, B. L.; Hartung,
W. H. J . Org. Chem. 1946, 11, 444. (c) Suschitzky, H. Adv. Fluorine
Chem. 1965, 4, 1. (d)Yakobson, G. G.; D’yachenko, A. I.; Bel’chikova,
F. A. Zh. Obshch. Khim. 1962, 32, 849 (translated).
(17) (a) Hino, T.; Uehara, H.; Takashima, M.; Kawate, T.; Seki, H.;
Hara, R.; Kuramochi, T.; Nakagawa, M. Chem. Pharm. Bull. 1990,
38, 2632. (b) Atwal, K. S.; Ferrare, F. N.; Ding, C. Z.; Grover, G. J .;
Sleph, P. G.; Dzwonczyk, S.; Baird, A. J .; Normandin, D. E. J . Med.
Chem. 1996, 39, 304. (c) Sandmeyer reaction: Tietze, L. F.; Nordmann,
G. Eur. J . Org. Chem. 2001, 3247.
(12) Doyle, M. P.; Siegfried, B.; Dellaria, J . F. J . Org. Chem. 1977,
42, 2426.
(13) (a) Blum, J .; Bergmann, E. D. J . Org. Chem. 1967, 32, 342. (b)
Doyle, M. P.; Bryker, W. J . J . Org. Chem. 1979, 44, 1572.
(14) Sircar, I.; Duell, B. L.; Cain, M. H.; Burke, S. E.; Bristol, J . A.
J . Med. Chem. 1986, 29, 2142.
(15) (a) Layer, R. W.; MacGregor, I. R. J . Org. Chem. 1956, 21, 1120.
(b) Matsumoto, T.; Hata, K. J . Am. Chem. Soc. 1957, 79, 5506. (c)
Bartmann, W.; Konz, E.; Ruger, W. J . Heterocycl. Chem. 1987, 24, 677.
10196 J . Org. Chem., Vol. 68, No. 26, 2003

mother liquor was separated and the aqueous layer was ex-
tracted several times with CHCl3. The organic fractions were
washed with brine and dried over MgSO4, filtered, and evapo-
rated to give N-(3-oxo-indan-4-yl)acetamide (13) as a white solid,
14 g (73%, 2 steps): 1H NMR (300 MHz, CDCl3) δ 10.43 (br s,
1H), 8.40 (d, J ) 8.1 Hz, 1H), 7.54 (t, J ) 7.8 Hz, 1H), 7.11 (dd,
J ) 7.5, 0.9 Hz, 1H), 3.12-3.09 (m, 2H), 2.74-2.70 (m, 2H), 2.24
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 209.2, 169.4, 155.8, 138.8,
136.9, 122.7, 120.5, 116.6, 36.4, 25.4, 25.1; HRMS m/z calcd for
2.71-2.67 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 203.9, 157.9,
135.1, 134.2, 132.4, 125.9, 119.5, 37.1, 25.0; HRMS m/z calcd
for C9H7BrO 209.9680, obsd 209.9687. Anal. Calcd for C9H7-
BrO: C, 51.22; H, 3.34. Found: C, 51.23; H, 3.18.
7-Iod oin d a n -1-on e (4). 7-Aminoindan-1-one (15; 0.68 g, 4.6
mmol) was dissolved in H2O (5 mL), acetic acid (5 mL), and HCl
(1.3 mL) at room temperature. A solution of NaNO2 (0.36 g, 5
mmol) in H2O (1.3 mL) was added at 0 °C for 5 min. A solution
of KI (0.81 g, 4.9 mmol) in H2O (1.3 mL) was added and the
mixture was heated at 60 °C for 1 h.17c The mixture was cooled
to room temperature and treated with solid NaHSO3. The
mixture was diluted with H2O and extracted with CH2Cl2, and
the organic solution was washed with sat. NaHCO3 and brine
and then dried over MgSO4. The mixture was filtered and
evaporated and the residue was purified on a column of silica
gel eluting with 40-50% EtOAc:hexane. 7-Iodoindan-1-one (4)
was obtained as a light yellow solid 0.5 g (43%). 1H NMR (300
MHz, CDCl3) δ 7.81 (d, J ) 7.8 Hz, 1H), 7.46 (d, J ) 7.5 Hz,
1H), 7.21 (t, J ) 7.5 Hz, 1H), 3.03 (t, J ) 6.0 Hz, 2H), 2.73-2.69
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 204.2, 157.9, 139.1, 136.2,
135.0, 126.7, 90.6, 37.2, 24.5; HRMS m/z calcd for C9H7IO
257.9542, obsd 257.9539. Anal. Calcd for C9H7IO: C, 41.89; H,
2.73. Found: C, 41.90; H, 2.68.
8-F lu or o-1-tetr a lon e (5). 8-Amino-1-tetralone (16)9 (see
Supporting Information) (0.62 g, 3.85 mmol) in acetone (10 mL,
anhydrous) was added to a mixture of NOBF4 (0.59 g, 5.1 mmol)
in acetone (10 mL) at -20 °C. After 45 min, more nitrosonium
tetraborofluorate (∼0.67 g, 5.73 mmol) was added to the mixture.
The reaction was continued (30 m) until TLC analysis showed
no starting material. The mixture was poured into anhydrous
CHCl3 (50 mL) and stirred for 30 min. The mixture was dried
over MgSO4 and the solvent was removed under vacuum. The
solids were added portion-wise to a solution of toluene at reflux.
Heating was continued for 15 min whereupon the mixture was
cooled to room temperature and filtered through Celite. The
solids were flushed with CHCl3 and the concentrated residue
was purified on a column of silica gel. The product was eluted
with 60% EtOAc:hexane to give 8-fluoro-1-tetralone (5) as a
yellow oil, 0.26 g (41%): 1H NMR (300 MHz, CDCl3) δ 7.39 (dt,
J ) 7.8, 4.8 Hz, 1H), 7.03 (d, J ) 7.5 Hz, 1H), 6.96 (dd, J ) 8.7,
11.4 Hz, 1H), 2.95 (t, J ) 5.7 Hz, 2H), 2.63 (t, J ) 6.3 Hz, 2H),
2.13-2.05 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 196.4, 164.1,
160.6, 147.0, 134.6, 124.6, 121.7, 115.3, 40.5, 30.2, 22.9; HRMS
m/z calcd for C10H9FO 164.0637, obsd 164.0646. Anal. Calcd for
C
11H11NO2 189.0790, obsd 189.0798. Anal. Calcd for C11H11-
NO2: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.94; H, 5.84; N,
7.37.
7-Am in oin d a n -1-on e (15). N-(3-Oxo-indan-4-yl)acetamide
(13; 14 g, 74 mmol) in 6 N HCl (200 mL) was heated at 90 °C
for 3 h. The mixture was cooled to room temperature and Na2-
CO3 was added in small portions followed by addition of 2 M
NaOH until the mixture was at pH 8. The aqueous layer was
extracted with EtOAc and the organic fractions were combined,
washed with brine, dried, filtered, and concentrated to give
7-aminoindan-1-one (15) as a yellow solid, 9.95 g (91%): 1H NMR
(300 MHz, CDCl3) δ 7.27 (t, J ) 7.2 Hz, 1H), 6.65 (d, J ) 7.2
Hz, 1H), 6.44 (dd, J ) 8.4, 0.6 Hz, 1H), 5.70 (br s, 2H), 3.00 (t,
J ) 6.0 Hz, 2H), 2.64-2.60 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 203.2, 151.3, 142.5, 131.4, 115.8, 108.9, 107.2, 31.4, 21.0;
HRMS m/z calcd for C9H9NO 147.0694, obsd 147.0684 Anal.
Calcd for C9H9NO: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.24;
H, 6.21; N, 9.49.
7-F lu or oin d a n -1-on e (1). 7-Aminoindan-1-one (15, 0.78 g,
5.3 mmol) in acetone (12 mL, anhydrous) was added to a mixture
of nitrosonium tetraborofluorate (NOBF4; 0.72 g, 6.2 mmol) in
acetone (10 mL) at -15 °C. After 30 min, more nitrosonium
tetraborofluorate (∼0.3 g, 2.57 mmol) was added to the mixture.
This was continued until the TLC showed the disappearance of
the starting material. The mixture was poured into anhydrous
CHCl3 (50 mL) and stirred for 30 min. The mixture was cooled
to 0 °C and the precipitate (diazonium borofluoride salt) was
removed by filtration. The precipitate (mp 67-69 °C) was
washed with hexane and dried under vacuum in a desiccator.16d
The salt was added portion-wise to a solution of toluene at 84
°C. Heating continued for 5.5 h. The mixture was cooled to room
temperature and loaded directly onto a column of silica gel. The
product was eluted (10% EtOAc:hexane to 20% EtOAc:hexane)
and 7-fluoroindan-1-one (1) was isolated as a yellow solid, 0.25
g (31%): 1H NMR (300 MHz, CDCl3) δ 7.52 (dt, J ) 5.1, 7.5 Hz,
3H), 7.22 (d, J ) 7.8 Hz, 1H), 6.93 (t, J ) 8.7 Hz, 1H), 3.12 (t, J
) 6.0 Hz, 2H), 2.70-2.65 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
203.3, 160.9, 157.5, 136.6, 124.9, 122.6, 114.1, 36.9, 25.9; HRMS
m/z calcd for C9H7FO 150.0481, obsd 150.0491 Anal. Calcd for
C9H7FO: C, 77.99; H, 4.70. Found: C, 71.71; H, 4.61.
7-Ch lor o-in d a n -1-on e (2). A mixture of CuCl2 (0.55 g, 4.1
mmol) and tert-butyl nitrite (0.67 mL, 5.07 mmol) in acetonitrile
(8 mL) at 65 °C was treated with 7-aminoindan-1-one (15; 0.46
g, 3.13 mmol) in acetonitrile (6 mL) over 10 min.12 The mixture
was concentrated onto silica gel (∼2 g) and purified by column
chromatography with 10% EtOAc:hexane to give 7-chloroindan-
1-one (2), 0.360 g (64%): 1H NMR (500 MHz, CDCl3) δ 7.44 (t,
J ) 8.0 Hz, 1H), 7.34 (d, J ) 7.0 Hz, 1H), 7.25 (d, J ) 7.5 Hz,
1H), 3.07 (t, J ) 6.0 Hz, 2H), 2.70-2.68 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 203.9, 157.7, 135.2, 133.1, 132.05, 129.2, 125.4,
37.1, 25.3; HRMS m/z calcd for C9H7ClO 166.0185, obsd 166.0187.
Anal. Calcd for C9H7ClO: C, 64.88; H, 4.23. Found: C, 64.77;
H, 4.12.
7-Br om oin d a n -1-on e (3). 7-Aminoindan-1-one (15; 0.5 g, 3.4
mmol) in HBr (48%, 1 mL) and EtOH (4 mL) at 0 °C was treated
with an aqueous solution of NaNO2 (0.31 g, 4.36 mmol in 0.54
mL of H2O) for 15 min. This mixture was added to a solution of
CuBr (0.27 g, 1.8 mmol) in HBr (∼5 mL) at 95 °C and kept at
this temperature for 15 min.17b The solution was cooled to room
temperature, diluted with water, and extracted with EtOAc. The
organic layers were washed with sat. NaHCO3, dried over
MgSO4, and purified by column chromatography with 40-50%
EtOAc:hexane on silica gel. 7-Bromoindan-1-one (3) was isolated
as a white solid, 0.42 g (60%): 1H NMR (300 MHz, CDCl3) δ
7.48-7.45 (m, 1H), 7.41-7.33 (m, 2H), 3.06 (t, J ) 6.0 Hz, 2H),
C
10H9FO: C, 73.16; H, 5.53. Found: C, 73.08; H, 5.53.
8-Ch lor o-1-tetr a lon e (6). A mixture of CuCl2 (2.0 g, 14.8
mmol) and tert-butyl nitrite (2.3 mL, 17.4 mmol) in acetonitrile
(830 mL) at 65 °C was treated with 8-amino-1-tetralone (16; 1.8
g, 11.1 mmol) in acetonitrile (15 mL). After 10 min, the mixture
was cooled, concentrated onto silica gel, and purified by column
chromatography with 10% EtOAc:hexane to give 8-chloro-1-
tetralone (6), 1.58 g (78%): 1H NMR (300 MHz, CDCl3) δ 7.27-
7.21 (m, 2H), 7.11-7.08 (m, 1H), 2.90 (t, J ) 6.0 Hz, 2H), 2.60
(t, J ) 6.0 Hz, 2H), 2.06-1.98 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 196.5, 147.1, 134.1, 132.7, 130.3, 129.8, 127.6, 40.4,
30.7, 22.6; HRMS m/z calcd for
C10H9ClO 180.3342, obsd
180.0339. Anal. Calcd for C10H9ClO: C, 66.49; H, 5.02. Found:
C, 66.24; H, 4.79.
8-Br om o-1-tetr a lon e (7). 8-Amino-1-tetralone (16; 0.65 g,
41 mmol) in HBr (48%, 1.2 mL) and EtOH (4.8 mL) at 0 °C was
treated with an aqueous solution of NaNO2 (0.35 g, 4.39 mmol
in 0.6 mL of H2O) for 15 min. This mixture was added via pipet
to a solution of CuBr (0.32 g, 2.2 mmol) in HBr (1.2 mL) at 95
°C and maintained at this temperature for 15 min. The solution
was cooled to room temperature, diluted with water, and
extracted with EtOAc. The organic layers were washed with sat.
NaHCO3, dried over MgSO4, and purified by column chroma-
tography with 10% EtOAc:hexane on silica gel. 8-Bromo-1-
tetralone (7) was isolated as a white solid, 0.65 g (70%): 1H NMR
(300 MHz, CDCl3) δ 7.50-7.44 (m, 1H), 7.16-7.14 (m, 2H), 2.91
(t, J ) 6.0 Hz, 2H), 2.62 (t, J ) 6.3 Hz, 2H), 2.07-1.98 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 196.6, 147.2, 133.9, 132.9, 130.9,
128.3, 121.8, 40.0, 30.8, 22.4; HRMS m/z calcd for C10H9BrO
223.9837, obsd 223.9828.
J . Org. Chem, Vol. 68, No. 26, 2003 10197

8-Iod o-1-tetr a lon e (8). 8-Amino-1-tetralone (16; 0.51 g, 3.16
mmol) was dissolved in H2O (4 mL), acetic acid (4 mL), and HCl
(1 mL). A solution of NaNO2 (0.25 g, 3.5 mmol) in H2O (0.5 mL)
was added at 0 °C for 5 min. A solution of KI (0.58 g, 3.5 mmol)
in H2O (1 mL) was added and the mixture was heated at 60 °C
for 1 h. The mixture was cooled to room temperature. Solid
NaHSO3 was added and the mixture was diluted with H2O and
extracted with CH2Cl2. The organic solution was washed with
sat. NaHCO3 and brine and dried over MgSO4. The mixture was
filtered and evaporated and residue was purified on a column
of silica gel eluting with 40% EtOAc:hexane. 8-Iodo-1-tetralone
(8) was obtained as a light pink solid, 0.51 g (60%): 1H NMR
(300 MHz, CDCl3) δ 7.86 (d, J ) 7.8 Hz, 1H), 7.18 (d, J ) 7.5
Hz, 1H), 6.96 (t, J ) 7.5 Hz, 1H), 2.91 (t, J ) 6.3 Hz, 2H), 2.64
(t, J ) 6.6 Hz, 2H), 2.07-1.99 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 196.7, 146.9, 141.6, 133.3, 132.5, 129.5, 93.2, 39.5, 31.2,
22.6; HRMS m/z calcd for C10H9CIO 271.9698, obsd 271.9692.
Anal. Calcd for C10H9CIO: C, 44.14; H, 3.33. Found: C, 43.88;
H, 3.13.
NaCl (75 g, 1.28 mol) at 130 °C. The mixture was stirred at 180
°C for 2 h, cooled to room temperature, and quenched with ice
followed by concentrated HCl. The resulting mixture was
extracted with CH2Cl2 and the combined extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure.
Column chromatography on silica gel with 25% EtOAc:hexane
as eluant gave 7-fluoro-1-indanone (1), 6.85 g (32%, over three
steps). See data for 1 above.
7-Ch lor oin d a n -1-on e (2). 2-Chlorobenzoic acid (18; 10.0 g,
0.64 mol), SOCl2 (7 mL, 0.096 mol), and AlCl3 (8.5 g, 0.064 mol)
were reacted with excess ethylene as above. This was followed
by reaction with an additional amount of AlCl3 (85 g, 0.64 mol)
and NaCl (22 g, 0.38 mol) in the procedure above, to give
7-chloro-1-indanone (2), 4.13 g (39%, over three steps). See data
for 2 above.
7-Br om oin d a n -1-on e (3). 2-Bromobenzoic acid (19; 30.0 g,
0.15 mol), SOCl2 (16.5 mL, 0.23 mol), and AlCl3 (20.0 g, 0.150
mol) were reacted with excess ethylene as above. This was
followed by reaction with an additional amount of AlCl3 (200 g,
1.5 mol) and NaCl (52 g, 0.89 mol) in the procedure above to
give 7-bromo-1-indanone (3), 9.68 g (31%, over three steps). See
data for 3 above.
E xp er im en t a l for Sch em e 2:14,15 7-F lu or o-in d a n -1-on e
(1). 2-Fluorobenzoic acid (17; 20.0 g, 0.14 mol) and thionyl
chloride (15.6 mL, 0.21 mol) in benzene were refluxed until no
more gas evolution was observed. After being cooled to room
temperature the mixture was concentrated under vacuum. The
mixture was diluted with dichloroethane and added to a solution
of AlCl3 (19.0 g, 0.14 mol) in dichloroethane at room temperature.
Ethylene was bubbled through the mixture for 4 h and the
mixture was stirred overnight. The mixture was quenched with
4 M HCl. The resulting layers were separated and the aqueous
layer was extracted with Et2O (3 × 250 mL). The combined
organic extracts were washed with H2O (3 × 150 mL), sat.
NaHCO3 (3 × 150 mL), and brine (1 × 150 mL), dried over
MgSO4 ,and freed of solvent under reduced pressure. The
material was added to a slurry of AlCl3 (286 g, 2.14 mol) and
Ack n ow led gm en t .
The authors acknowledge
Michael Roof for structural confirmations (regioselec-
tivity issues) by 2D NMR.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of 8-amino-1-tetralone (16)9 and
spectral data for 7 and 11. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O035289S
10198 J . Org. Chem., Vol. 68, No. 26, 2003