Concise syntheses of 2-aminoindans via indan-2-ol

Article abstract of DOI:10.1016/j.tet.2005.04.069

2-Amino-5,6-dimethoxyindan hydrochloride was synthesized in seven steps and with an overall yield of 48%. Indan-2-ol was converted to 5,6-dibromo-indan-2- ol in three steps by acetylation, electrophilic bromination and deacetylation. Dimethoxylation of 5,6-dibromoindan-2-ol with NaOCH₃ in the presence of CuI gave 5,6-dimethoxy-indan-2-ol, which was converted to 2-amino-5,6-dimethoxyindan hydrochloride by azidation, followed by Pd-C catalyzed hydrogenation. Similarly, 2-amino-5-bromoindan was synthesized in five steps and with an overall yield of 50%. Indan-2-ol was converted to 2-aminoindan by azidation followed by Pd-C catalyzed hydrogenation. The reaction of 2-aminoindan with 2.5 equiv Br₂ afforded 2-amino-5,6- dibromoindan.

Full text of DOI:10.1016/j.tet.2005.04.069

Tetrahedron 61 (2005) 6801–6807
Concise syntheses of 2-aminoindans via indan-2-ol
*
¨
Su¨leyman Goksu and Hasan Sec¸en
Department of Chemistry, Faculty of Arts and Sciences, Ataturk University, 25240 Erzurum, Turkey
Received 30 January 2005; revised 8 April 2005; accepted 29 April 2005
Abstract—2-Amino-5,6-dimethoxyindan hydrochloride was synthesized in seven steps and with an overall yield of 48%. Indan-2-ol was
converted to 5,6-dibromo-indan-2-ol in three steps by acetylation, electrophilic bromination and deacetylation. Dimethoxylation of 5,6-
dibromoindan-2-ol with NaOCH3 in the presence of CuI gave 5,6-dimethoxy-indan-2-ol, which was converted to 2-amino-5,6-
dimethoxyindan hydrochloride by azidation, followed by Pd–C catalyzed hydrogenation. Similarly, 2-amino-5-bromoindan was synthesized
in five steps and with an overall yield of 50%. Indan-2-ol was converted to 2-aminoindan by azidation followed by Pd–C catalyzed
hydrogenation. The reaction of 2-aminoindan with 2.5 equiv Br2 afforded 2-amino-5,6-dibromoindan.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
dihydroxyindans, including compounds 3–6, and reported
that certain N-alkylated 4,5-dihydroxyindanes were violent
emetics in the dog, and were potent in blockade of the effect
of stimulation of the cardioaccelarator nerve in the cat.
Aminoindan 3 has been reported to have a-adrenergic
effects4 and covalent binding5 to Src family SH2 domains.
The hydrochloride salt of 4 has been reported to be useful as
an analgesic.6 5,6-Dimethoxy-2-(N-dipropyl)-aminoindan
(5), PNU-99194A, has been reported to be a selective
dopamine D3 receptor antagonist with potential
The neurotransmitter dopamine (1) plays a central role in
central nervous system (CNS)-related disorders such as
schizophrenia and Parkinson’s disease.1 In recent years
many chemical compounds have been found to possess
dopamine-like actions. It has been suggested that 6,7-ADTN
(2), a dopamine-like compound, interacts with the dopamine
receptor with slightly greater affinity than dopamine itself.2
Cannon et al.3 have synthesized a series of 2-amino-4,5-
Keywords: 2-Aminoindans; Synthesis; 2-Azidoindans; 2-Indanols; Mitsunobu reaction; Dopamine.
*
Corresponding author. Tel.: C90 442 2314408; fax: C90 442 2360948; e-mail: sgoksu@atauni.edu.tr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.069

¨
S. Goksu, H. Sec¸en / Tetrahedron 61 (2005) 6801–6807
6802
antipsychotic properties in animal models.7 Some valuable
papers have recently appeared on the pharmacological
actions of compound 5.8
hydrolyzed to alcohol 14 with NaOH in H2O–MeOH.
Esterification of alcohol 14 with MeSO2Cl and substitution
of the corresponding mesylate with NaN3 in DMF afforded
2-azido-5,6-dimethoxyindan (15). The reduction of azide 15
with Pd–C catalyzed hydrogenation in the presence of
The synthesis of 5,6-dimethoxy-2-aminoindan (4) from
3-(3,4-dimethoxyphenyl)-propionic acid has been
described3,7 in six steps with an overall yield of 38%. In
our ongoing project on the synthesis of biologically active
dopamine-like compounds, we reported a concise synthesis
of 6,7-ADTN (2).9 In the present study we performed an
alternative and concise synthesis of 2-amino-5,6-
dimethoxyindan (4) from indan-2-ol, a commercially
available reagent much cheaper than 3-(3,4-dimethoxy-
phenyl)-propionic acid, in seven steps and with a 48% total
yield. On the other hand, 2-amino-5-bromoindan (7) is an
important precursor of LAB687 (8), which is an inhibitor of
microsomal triglyceride transfer protein (MTP).10 In the
present study we also performed an alternative preparation
of 7, starting from indan-2-ol in five steps and with a 50%
total yield.
12
CHCl3 in MeOH gave 2-amino-5,6-dimethoxyindan
hydrochloride (16) (Scheme 1). The preparation of N,N-
dialkyl derivatives from the free base of 5,6-dimethoxy-2-
aminoindan (16), including PNU-99194A (5), was
previously well defined.3,7
Our next purpose in this study was to develop an alternative
synthesis of 2-amino-5-bromoindan (7), starting from
indan-2-ol (9). To our knowledge, different syntheses of 7
have been reported in the literature. One of these procedures
uses 1-bromo-4-(bromomethyl)benzene as the starting
material and includes a many-step reaction.13 The other
procedure uses the bromination of commercially available
2-aminoindan in one step and with 65% yield.10b However,
2-aminoindan is 25 times more expensive than indan-2-ol
(9). Therefore, we developed an alternative method for the
synthesis of 2-amino-5-bromoindan (7).
2. Results and discussion
The first step of the synthesis was the bromination of indan-
2-ol acetate 10 with NBS in acetonitrile and in the dark to
give monobromide 17. Hydrolysis of 17 with NaOH in
MeOH–H2O gave 5-bromo-indan-2-ol (18). In our previous
studies we reported14 the conversion of some epoxides,
trans-1,2-diols, and azidoalcohols to the corresponding
azide compounds via the Mitsunobu reaction with DEAD,
PPh3 and HN3. A similar procedure applied to alcohol 18
gave bromoazide 19. Prashad et al.10b have reported that
Pd–C catalyzed hydrogenolysis of 2-amino-5-bromoindan
gave 2-aminoindan. Therefore, we had to choose a reagent
that would reduce only the azide functional group. Although
the reduction of azides with LiAlH4 to give the correspond-
ing amines has been well defined,15 this method resulted in a
product mixture including debrominated 19, which was not
characterized. The reduction of bromoazide 19 with
The reaction of indan-2-ol (9) with AcCl gave indan-2-ol
acetate (10). The bromination of 10 with NBS–Br2 in
acetonitrile in the dark gave dibromoacetate 11 and the
hydrolysis of 11 with NaOH in H2O/MeOH gave 5,6-
dibromoindan-2-ol (12). The most critical step of our
synthesis was the substitution of the bromines in compound
12 with NaOMe. Copper-assisted nucleophilic substitutions
of aryl halogens are described in the literature.11 Consider-
ing the applicability of the reaction, we assumed that the
methoxylation of 12 would proceed with the substitution of
bromide with methoxide. Indeed, the reaction of 12 with
NaOMe in the presence of CuI in a mixture of MeOH and
DMF gave the expected dimethoxide 14 which was
converted to its acetate derivative 13 by acetylation with
AcCl for further purification. Then, acetate 13 was
Scheme 1. (i) AcCl, 0–25 8C. (ii) NBS (2 equiv), Br2 (1.1 equiv), CH3CN, 0–25 8C, in darkness. (iii) 10% aq NaOH, MeOH, 0–25 8C. (iv) NaOMe, CuI (cat.),
DMF, MeOH, reflux, 90 8C, then AcCl, 0–25 8C. (v) 10% aq NaOH, MeOH, 0–25 8C. (vi) MeSO2Cl, NEt3, CH2Cl2, 25 8C, then NaN3, DMF, reflux. (vii) Pd–C
(cat.), H2, CHCl3, MeOH.

¨
S. Goksu, H. Sec¸en / Tetrahedron 61 (2005) 6801–6807
6803
Scheme 2. (i) NBS, CH3CN, 25 8C. (ii) 10% aq NaOH, MeOH, 0–25 8C. (iii) DEAD, PPh3, HN3, 0–25 8C. (iv) NaBH4, CuSO4 (cat.), MeOH, 0–25 8C. (v) 36%
HBr, MeOH, 0 8C.
Scheme 3. (i) DEAD, PPh3, HN3, THF, 0–25 8C. (ii) NaBH4 (2.1 equiv), CuSO4 (cat.), MeOH, 0–25 8C.
CuSO4$5H2O–NaBH4 as described by Rao and Siva16 gave
the corresponding 2-amino-5-bromoindan (7) with a good
yield, which was converted to its HBr salt 2010b for further
characterization (Scheme 2).
HN3) gave 2-azidoindan (22). The reduction of azide 22
with Pd–C catalyzed hydrogenation in MeOH in the
presence of CHCl3 afforded 2-aminoindan hydrochloride
(23). The bromination of 23 with 2.5 equiv of Br2 in H2O
gave 2-amino-5,6-dibromoindan hydrobromide (24)
(Scheme 4).
We supposed that 5,6-dibromoindan-2-ol (12) could be used
as an important precursor for LAB687 (8) type compounds.
Therefore, we converted alcohol 12 to the corresponding
azide 21 under Mitsunobu conditions as before. Our
attempts to reduce azide 21 with hydride reagents to yield
2-amino-5,6-dibromoindan failed. While the reduction of 21
with 1 equiv LiAlH4 gave 2-aminoindan, the reduction of 21
with 1 equiv of NaBH4 gave an inseparable mixture
containing 2-amino-5,6-dibromoindan, 2-amino-5-
bromoindan and unreacted 21. However, following a
literature procedure,16 the reduction of 21 with 2 equiv
NaBH4 in the presence of CuSO4 within 3 h gave 2-amino-
5-bromoindan (7) as the sole product (Scheme 3). If we use
2 equiv NaBH4 in the presence of CuSO4 and extend the
reaction time, we observed that azide group and two
bromide group may be reduced.
3. Conclusion
Starting from indan-2-ol, we describe a concise synthesis of
2-amino-5,6-dimethoxyindan, an important precursor for
selective dopamine D3 receptor antagonist drugs, and an
alternative synthesis of 2-amino-5-bromoindan, an import-
ant precursor of LAB687 (8) type compounds. We also
describe the first synthesis of 2-amino-5,6-dibromo-indan,
which can be used for the synthesis of biologically active
compounds.
4. Experimental
4.1. General information
For the synthesis of 2-amino-5,6-dibromoindan, we chan-
ged our strategy. In the second strategy, the reaction of
indan-2-ol (9) with the Mitsunobu reagents (DEAD, PPh3,
Solvents were purified and dried by standard procedures
Scheme 4. (i) DEAD, PPh3, HN3, THF, 0–25 8C. (ii) Pd–C (cat), H2, CHCl3, MeOH. (iii) Br2, H2O, 50–60 8C.

¨
S. Goksu, H. Sec¸en / Tetrahedron 61 (2005) 6801–6807
6804
before use. Melting points were determined on a Bu¨chi 539
capillary melting apparatus and are uncorrected. Infrared
spectra were obtained from KBr or film on a Mattson 1000
(16), 131.0 (28), 114.0 (18), 104.0 (32), 103.0 (64), 102.0
(54), 78.0 (18), 77.0 (46).
1
FT-IR spectrophotometer. The H and 13C NMR spectra
4.1.4. 5,6-Dimethoxyindan-2-ol acetate (13). To refluxing
MeOH (70 mL) was added Na (3.15 g, 137.0 mmol) in
small pieces over 1 h under N2. To the solution was added
5,6-dibromoindan-2-ol (12) (10.00 g, 34.2 mmol) in freshly
distilled DMF (40 mL). While the reaction mixture was
being heated at reflux, CuI (approximately 100–150 mg)
was added. After heating for 20 h, the reaction mixture was
cooled to rt. After the removal of MeOH under reduced
pressure H2O (50 mL) and CH2Cl2 (100 mL) were added
and the organic layer was separated. The organic layer was
washed with H2O (3!50 mL) and dried (Na2SO4). After
evaporation of the solvent, the residue was reacted with
AcCl at rt for 16 h. After evaporation of the excess AcCl, the
residue was filtered on a short silica gel column (10 g),
eluting with CH2Cl2. Evaporation of the solvent gave 5,6-
dimethoxyindan-2-ol acetate (13) (6.55 g, 81%) Colorless
crystals. Mp 71–73 8C (CH2Cl2–hexane). 1H NMR
(200 MHz, CDCl3) d 6.76 (s, 2H, H-4 and H-7), 5.50 (tt,
1H, H-2, JZ6.6, 3.0 Hz), 3.84 (s, 6H, 2!OCH3), 3.25 (A
part of AB system, dd, 2H, JZ16.6, 6.6 Hz), 2.92 (B part of
AB system, dd, 2H, JZ16.6, 3.0 Hz), 2.01 (s, 3H,
C(O)CH3). 13C NMR (50 MHz, CDCl3) d 170.8, 148.5,
131.9, 108.0, 75.6, 56.0, 39.5, 21.1. IR (KBr) 3068, 2996,
2940, 2834, 1735, 1611, 1507, 1466, 1455, 1443, 1374,
1315, 1240, 1190, 1090, 1025. Anal. Calcd for C13H16O4
(236.3): C, 66.09; H, 6.83; Found: C, 65.77; H, 6.95.
were recorded on 400 (100) or 200 (50) MHz Varian
spectrometers. Elemental analyses were carried out with a
Leco CHNS-932 instrument. EI-MS spectra were recorded
on a Thermo-Finnigan mass analyzer. Column chromato-
graphy was performed on silica gel 60 (70–230 mesh
ASTM). Thin layer chromatography was carried out on
Merck 0.2 mm silica gel, and 60 F254 analytical aluminum
plates.
4.1.1. Indan-2-ol acetate (10). AcCl (30 mL) was added
dropwise to indan-2-ol (9) (10.00 g, 74.6 mmol) at 0 8C.
After the addition was completed the mixture was stirred at
rtfor16 h.TheevaporationoftheexcessAcClgaveindan-2-ol
1
acetate (10)17 as a clear oil (13.13 g, 100%). H NMR is in
agreement with the literature.17 13C NMR (50 MHz, CDCl3) d
170.6, 140.3, 126.5, 124.5, 75.2, 23.5, 21.0.
4.1.2. 5,6-Dibromoindan-2-ol acetate (11). To a stirred
solution of indan-2-ol acetate (10) (10.00 g, 56.8 mmol) in
freshly distilled acetonitrile (300 mL) from P2O5 was added
NBS (20.23 g, 113.6 mmol) and Br2 (10.00 g, 62.5 mmol) at
25 8C in darkness. The mixture was stirred at rt in darkness
for 5 days. The solvent and excess Br2 were evaporated. The
residue was dissolved in 150 mL of CH2Cl2 and the organic
layer was washed with 3!100 mL of saturated Na2CO3
solution. The organic layer was dried from Na2SO4 and the
solvent was evaporated. Chromatography of the crude
product on a short silica gel column (20 g), eluting with
hexane–EtOAc (4:1), gave 5,6-dibromoindan-2-ol acetate
(11) (16.00 g, 84%). Clear oil. 1H NMR (200 MHz, CDCl3)
d 7.47 (bs, 2H, H-4 and H-7), 5.49 (tt, 1H, H-2, JZ6.3,
2.8 Hz), 3.24 (A part of AB system, ddd, 2H, JZ17.4, 6.3,
1.0 Hz), 2.93 (B part of AB system, dd, 2H, JZ17.4,
2.8 Hz), 2.01 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3) d
170.6, 141.8, 129.6, 122.6, 75.0, 39.1, 21.1. IR (CH2Cl2)
3056, 2968, 2910, 2852, 1739, 1466, 1428, 1374, 1247,
1100. Anal. Calcd for C11H10Br2O2 (334): C, 39.56; H,
3.02; Found: C, 39.88; H, 2.84.
4.1.5. 5,6-Dimethoxyindan-2-ol (14). The hydrolysis
procedure above described for 5,6-dibromo-indan-2-ol
acetate (11) in 4.1.3 was applied to 5,6-dimethoxyindan-2-
ol acetate (13) to give 5,6-dimethoxyindan-2-ol (14) (90%).
Colorless crystals. Mp 68–70 8C (from CH2Cl2–hexane). 1H
NMR (200 MHz, CDCl3) d 6.74 (s, 2H, H-4 and H-7), 4.61
(tt, 1H, H-2, JZ5.9, 3.3 Hz), 3.81 (s, 6H, 2!OMe), 3.10 (A
part of AB system, dd, 2H, JZ15.9, 5.9 Hz), 2.78 (B part of
AB system, dd, 2H, JZ15.9, 3.3 Hz), 2.60 (bs, 1H, OH). 13C
NMR (50 MHz, CDCl3) d 148.1, 132.3, 108.2, 73.2, 55.9,
42.4. IR (KBr) 3393, 2996, 2937, 2833, 1610, 1465, 1454,
1311, 1244, 1186, 1088. Anal. Calcd for C11H14O3 (194.1):
C, 68.02; H, 7.27; Found: C, 67.85; H, 7.19. EIMS m/e (%):
194.9 (MC, 8), 193.8 (MC, 78), 175.8 (28), 164.8 (100),
160.7 (22), 150.7 (18), 132.7 (12), 122.7 (10).
4.1.3. 5,6-Dibromoindan-2-ol (12). To a stirred solution of
5,6-dibromoindan-2-ol acetate (11) (10.00 g, 29.9 mmol) in
MeOH (80 mL) was added 10% aqueous NaOH (20 mL)
and the mixture was stirred at rt for 15 h. After the
evaporation of the MeOH, 50 mL of H2O was added and
the organic layer was extracted with CH2Cl2 (3!50 mL).
The organic layer was dried (Na2SO4) and evaporation of
the solvent gave 5,6-dibromoindan-2-ol (12) (7.87 g, 90%).
Colorless crystal. Mp 130–132 8C (from CH2Cl2–Hexane).
1H NMR (200 MHz, CDCl3) d 7.51 (bs, 2H, H-4 and H-7),
4.72 (tt, 1H, H-2, JZ5.9, 3.0 Hz), 3.16 (A part of AB
system, dd, 2H, JZ16.8, 5.9 Hz), 2.86 (B part of AB
system, dd, 2H, JZ16.8, 3.0 Hz), 1.86 (s, 1H, OH). 13C
NMR (50 MHz, CDCl3) d 142.2, 129.9, 122.4, 73.1, 42.1.
IR (KBr) 3287, 2933, 2825, 1458, 1420, 1351, 1285, 1254,
1200, 1100. Anal. Calcd for C9H8Br2O (292.0): C, 37.02; H,
2.76; Found: C, 36.86; H, 2.74. EIMS m/e (%): 293.9 (MC,
16), 291.8 (MC, 36), 289.9 (MC, 18), 264.8 (50), 262.8
(100), 260.8 (56), 192.9 (20), 183.0 (24), 181.9 (20), 132.0
4.1.6. 2-Azido-5,6-dimethoxyindan (15). To a stirred
solution of 5,6-dimethoxyindan-2-ol (14) (1.40 g,
7.2 mmol) and NEt3 (0.88 g, 8.7 mmol) in CH2Cl2
(30 mL) was added a solution of MeSO2Cl (1.83 g,
15.9 mmol) in CH2Cl2 dropwise at 0 8C over 15 min. The
mixture was stirred at rt for 3.5 h. After the filtration of the
reaction mixture and removal of the solvent of the filtrate,
freshly distilled DMF (30 mL) and NaN3 (1.41 g,
21.7 mmol) were added. The reaction mixture was stirred
at 120 8C for 18 h. The reaction mixture was cooled to rt and
H2O (50 mL) and CH2Cl2 (60 mL) were added. The organic
layer was separated and washed with H2O (3!50 mL). The
organic layer was dried over Na2SO4 and CH2Cl2 was
evaporated. Chromatography of the crude product on a short
silica gel column (15 g), eluting with CH2Cl2, gave 2-azido-
1
5,6-dimethoxyindan (15) (1.42 g, 90%). Colorless oil. H
NMR (200 MHz, CDCl3) d 6.77 (s, 2H, H-4 and H-7), 4.34

¨
S. Goksu, H. Sec¸en / Tetrahedron 61 (2005) 6801–6807
6805
(tt, 1H, H-2, JZ6.6, 4.2 Hz), 3.85 (s, 6H, 2!OCH3), 3.18
(A part of AB system, dd, 2H, JZ15.8, 6.6 Hz), 2.93 (B part
of AB system, dd, 2H, JZ15.8, 4.2 Hz). 13C NMR
(50 MHz, CDCl3) d 148.5, 131.6, 107.8, 62.0, 56.0, 38.9.
IR (CDCl3) 3070, 2997, 2937, 2833, 2110, 1610, 1504,
1465, 1454, 1313, 1265, 1230, 1189, 1089.
of AB system, dd, 1H, JZ16.5, 5.9 Hz), 2.88 (B part of AB
system, dd, 1H, JZ16.5, 3.1 Hz), 2.84 (B part of AB
system, dd, 1H, JZ16.6, 3.2 Hz), 2.05 (bs, 1H, OH). 13C
NMR (50 MHz, CDCl3) d 143.3, 139.8, 129.7, 128.1, 126.4,
120.3, 73.1, 42.6, 42.2. IR (KBr) 3295, 3064, 2948, 2894,
2817, 1601, 1574, 1474, 1420, 1412, 1343, 1293, 1258,
1197, 1162. Anal. Calcd for C9H9BrO (213.1): C, 50.73; H,
4.26; Found: C, 50.52; H, 4.11. EI-MS: 214.0 (MC, 40%),
212.0 (MC, 42%), 185.0 (MC, 98%), 183.0 (100%), 115.0
(30%), 105.1 (32%), 104.1 (22%), 77.0 (24%).
4.1.7. 2-Amino-5,6-dimethoxyindan hydrochloride (16).
Into a 100-mL flask were placed Pd–C (50 mg) and 2-azido-
5,6-dimethoxyindan (15) (1.00 g, 4.6 mmol) in MeOH
(35 mL) and CHCl3 (2 mL). A balloon filled with H2 gas
(3 L) was fitted to the flask. The mixture was deoxygenated
by flushing with H2 and then hydrogenated at rt for 20 h.
The catalyst was removed by filtration. Recrystallization of
the residue from MeOH–Et2O gave 2-amino-5,6-
dimethoxyindan hydrochloride (16) (1.00 g, 95%). Color-
less crystal. Mp 287–289 8C (from MeOH–Et2O), lit.3 Mp
288–290 8C (from 2-PrOH–Et2O). 1H NMR (200 MHz,
D2O) d 6.97 (s, 2H, H-4 and H-7). 4.23 (tt, 1H, H-2, JZ7.3,
3.7 Hz), 3.83 (s, 6H, 2!OCH3), 3.35 (A part of AB system,
dd, 2H, JZ16.9, 7.3 Hz), 2.98 (B part of AB system, dd, 2H,
JZ16.9, 3.7 Hz). 13C NMR (50 MHz, D2O) d 152.2, 135.7,
112.8, 60.2, 56.4, 41.6. Anal. Calcd for C11H16NO2Cl
(229.7): C, 67.52; H, 7.02; N, 6.10 Found: C, 57.85; H, 7.12;
N, 5.91.
4.1.10. Mitsunobu reaction of 5-bromo-indan-2-ol (18):
2-azido-5-bromoindan (19). The literature procedure14a
described for the conversion of trans-diols to the corre-
sponding diazides was applied to 5-bromo-indan-2-ol (18).
To a stirred solution of PPh3 (3.2 g, 12.2 mmol) in THF
(20 mL) was added a solution of DEAD (1.97 g, 11.3 mmol)
in THF (10 mL) dropwise under N2 1a8tm at 0 8C. To this
mixture was added a solution of HN3 (12.6 mmol, 7 mL,
1.8 M) and a solution of 5-bromoindan-2-ol (18) (2.00 g,
9.4 mmol) in THF (15 mL). The reaction mixture was
stirred at 0 8C for 30 min and then stirred at rt for 12 h. The
solvent of the reaction mixture was evaporated at 30 8C. The
residue was dissolved in 100 mL of Et2O and left in a
refrigerator overnight. After the filtration of the precipitate,
the solvent was evaporated. Chromatography of the residue
on a silica gel column (15 g) eluting with hexane–Et2O–
CHCl3 (100:7:7) gave 2-azido-5-bromoindan (19) (1.88 g,
84%). Colorless oil. 1H NMR (200 MHz, CDCl3) d 7.40 (bs,
4.1.8. 5-Bromoindan-2-ol acetate (17). To a stirred
solution of indan-2-ol acetate (10) (10.00 g, 56.8 mmol) in
freshly distilled acetonitrile (300 mL) from P2O5 was added
N-bromo-succinimide (30.34 g, 170.4 mmol) at rt in dark-
ness. The mixture was stirred at rt in darkness for 7 days.
The solvent was evaporated and the mixture was dissolved
in 150 mL of CH2Cl2. The organic layer was washed with
saturated aqueous Na2CO3 solution (3!100 mL). The
organic layer was dried over Na2SO4 and the solvent was
evaporated. Chromatography of the crude product on a short
silica gel column (15 g), eluting with hexane–EtOAc (4:1),
gave 5-bromoindan-2-ol acetate (17). (12.00 g, 83%).
Colorless crystal. Mp 75–77 8C (from CH2Cl2–hexane).
1H NMR (200 MHz, CDCl3) d 7.30 (bs, 1H, H-4), 7.32 (A
part of AB system, dd, 1H, H-6, J6,7Z8.0 Hz, J4,6Z1.6 Hz),
7.11 (B part of AB system, 1H, H-7, d, J6,7Z8.0 Hz),
5.53 (m, 1H, H-2), 3.29 (A part of AB system, dd, 1H, JZ
17.2, 6.4 Hz), 3.26 (A part of AB system, dd, 1H, JZ17.2,
6.6 Hz), 3.01 (B part of AB system, dd, 1H, JZ17.2,
3.0 Hz), 2.97 (B part of AB system, dd, 1H, JZ17.2,
3.0 Hz), 2.04 (s, 3H). 13C NMR (50 MHz, CDCl3) d 170.7,
142.0, 139.4, 129.0, 127.8, 126.0, 120.5, 75.1, 39.5, 39.1,
22.1. IR (CH2Cl2) 2968, 2921, 1736, 1470, 1420, 1370,
1254, 1197 cmK1. Anal. Calcd for C11H11BrO2 (254.0): C,
51.79; H, 4.35; Found: C, 51.51; H, 4.32. EI-MS: 195.9
(MCKCH3COOH, 38%), 193.9 (MCKCH3COOH, 40%),
115.0 (100%).
1H, H-4), 7.35 (A part of AB system, dd, 1H, H-6, J6,7
Z
8.1 Hz, J4,6Z1.9 Hz), 7.14 (B part of AB system, d, 1H,
H-7, J6,7Z8.1 Hz), 4.38 (m, 1H, H-2), 3.24 (A part of AB
system, dd, 1H, JZ16.5, 7.5 Hz), 3.20 (A part of
AB system, dd, 1H, JZ16.5, 6.9 Hz), 3.01 (B part of AB
system, dd, 1H, JZ16.5, 4.1 Hz), 2.98 (B part of AB
system, dd, 1H, JZ16.5, 4.1 Hz). 13C NMR (50 MHz,
CDCl3) d 142.3, 139.0, 129.8, 127.6, 125.9, 120.4, 61.5,
38.7, 38.6. IR (film) 3068, 2941, 2837, 2110, 1601, 1470,
1431, 1316, 1266, 1208, 1170 cmK1
.
4.1.11. 2-Amino-5-bromoindan (7).13 (a) From 2-azido-5-
bromoindan (19). To a stirred solution of CuSO4$5H2O
(0.11 g, 0.042 mmol) in 12 mL of MeOH was added NaBH4
(0.046 g, 1.24 mmol) at 0 8C. The reaction mixture was
stirred at the same temperature for 15 min. To this mixture
was added a solution of 2-azido-5-bromoindan (19) (1.00 g,
4.2 mmol) in 10 mL of MeOH and then NaBH4 (0.114 g,
3.00 mmol) in four portions over 1.5 h. After the addition of
NaBH4 was completed, the stirring was continued and
monitored by TLC at rt for 3 h. After the precipitate was
filtered off, MeOH was evaporated and the mixture was
made sufficiently alkaline (pHZ12) with 3 M NaOH. The
organic phase was extracted with EtOAc (3!25 mL). The
drying of the organic layer over Na2SO4 and evaporation of
EtOAc gave oily 2-amino-5-bromoindan (7) (0.71 g, 80%).
4.1.9. 5-Bromoindan-2-ol (18). The hydrolysis procedure
above described for 5,6-dibromo-indan-2-ol acetate (11)
was applied to 5-bromoindan-2-ol acetate (17) to give
5-bromoindan-2-ol (18) (90%). Colorless crystal. Mp 115–
117 8C (from CH2Cl2–hexane). 1H NMR (200 MHz,
CDCl3) d 7.38 (bs, 1H, H-4), 7.31 (A part of AB system,
dd, 1H, H-6, J6,7Z8.1 Hz, J4,6Z2.1 Hz), 7.12 (B part of AB
system, d, 1H, H-7, J6,7Z8.1 Hz), 4.68 (m, 1H, H-2), 3.19
(A part of AB system, dd, 1H, JZ16.6, 5.8 Hz), 3.14 (A part
(b) From 2-azido-5,6-dibromoindan (21). The procedure
above was applied to 2-azido-5,6-dibromoindan (21) using
2 equiv NaBH4 to give 2-amino-5-bromoindan (7) in a yield
of 75%.
For 7: 1H NMR (200 MHz, DMSO-d6) d 7.48 (bs, 1H, H-4),
7.37 (A part of AB system, d, 1H, H-6, J6,7Z8.1 Hz), 7.23

¨
S. Goksu, H. Sec¸en / Tetrahedron 61 (2005) 6801–6807
6806
(B part of AB system, d, 1H, H-7, J6,7Z8.1 Hz), 6.23 (bs,
2H, NH2), 3.97 (quasi quintet, 1H, H-2, JZ6.8 Hz), 3.28 (A
part of AB system, dd, 1H, JZ16.8, 8.1 Hz), 3.23 (A part of
AB system, dd, 1H, JZ16.8, 7.7 Hz), 3.04 (B part of AB
system, dd, 1H, JZ16.8, 5.9 Hz), 2.98 (B part of AB
system, dd, 1H, JZ16.8, 5.6 Hz). 13C NMR (50 MHz,
DMSO-d6) d 144.8, 141.3, 131.4, 129.3, 128.4, 121.5, 52.4,
39.1, 38.8. IR (film): 3352, 3274, 3048, 3021, 2939, 2901,
2835, 1597, 1571, 1468, 1431, 1407, 1385, 1314, 1247,
38.5. Anal. Calcd for C9H10Br3N (371.9): C, 29.07; H, 2.71;
N, 3.77; Found: C, 29.11; H, 2.68; N, 3.79.
Acknowledgements
We thank Ataturk University (Project number: 2004/177)
and State Planning Organization (Grade No: DPT
2004K/02) for their financial supports of this work, Assoc.
1206, 1166 cmK1
.
˘
Prof. Dr. Nurullah Sarac¸oglu for his helpful discussion. We
also thank Dr. Cavit Kazaz for taking NMR spectra, Dr.
Hamdullah Kılıc¸ for EI-MS spectra and Ebru Mete for
elemental analysis.
4.1.12. 2-Amino-5-bromoindan hydrobromide (20). To a
stirred solution of 2-amino-5-bromoindan (7) (0.50 g,
2.4 mmol) in MeOH (10 mL) was added HBr solution
(47%, 10 mL) at 0 8C. MeOH and excess HBr were
evaporated. The residue was recrystallized from MeOH–
ether to give 2-amino-5-bromoindan hydrobromide (20)
(0.56 g, 81%).Yellowish crystal. MpO290 8C (lit.10b MpO
300 8C). The 1H NMR is in agreement with the literature.10b
13C NMR (50 MHz, DMSO-d6) d 144.6, 141.1, 131.5,
129.4, 128.5, 121.6, 52.3, 38.9, 38.6.
References and notes
1. Haadsma-Svensson, S. R.; Svensson, K. A. CNS Drug Rev.
1998, 4, 42–53.
2. Cannon, J. G. Prog. Drug Res. 1985, 29, 303–414.
3. Cannon, J. G.; Perez, J. A.; Bhatnagar, R. K.; Long, J. P.;
Sharabi, F. M. J. Med. Chem. 1982, 25, 1442–1446.
4. Gray, A. P.; Reit, E.; Ackerly, J. A. J. Med. Chem. 1973, 16,
1023–1027.
4.1.13. 2-Azido-5,6-dibromoindan (21). The procedure
above described for the synthesis of 2-azido-5-bromoindan
(19) applied to 5,6-dibromoindan-2-ol (12) to give 2-azido-
1
5,6-dibromoindan (21) in a yield of 83%. Colorless oil. H
NMR (200 MHz, CDCl3) d 7.48 (s, 2H, H-4 and H-7), 4.37
(tt, 1H, H-2, JZ6.6, 4.1 Hz), 3.18 (A part of AB system,
ddd, 2H, JZ16.7, 6.6, 0.9 Hz), 2.93 (B part of AB system,
dd, 2H, JZ16.7, 4.1 Hz). 13C NMR (50 MHz, CDCl3) d
141.4, 129.6, 122.7, 51.7, 38.5. IR (film) 3068, 2941, 2844,
5. Jagoe, C. T.; Kreifels, S. E.; Li, J. Bioorg. Med. Chem. Lett.
1997, 7, 113–116.
6. Richter, H.; Schenck, M., German Patent 952441, 1956; Chem.
Abstr., 1959, 53, 2190e.
7. Haadsma-Svensson, S. R.; Cleek, K. A.; Dinh, D. M.; Duncan,
J. N.; Haber, C. L.; Huff, R. M.; Lajiness, M. E.; Nichols, N. F.;
Smith, M. W.; Svensson, K. A.; Zaya, M. J.; Carlsson, A.; Lin,
C. H. J. Med. Chem. 2001, 44, 4716–4732.
2113, 1466, 1431, 1266, 1104 cmK1
.
4.1.14. 2-Azidoindan (22). The procedure above described
for the synthesis of 2-azido-5-bromoindan (19) applied to
indan-2-ol (9) to give 2-azidoindan (22) in a yield of 86%.
Colorless oil. The 1H NMR is in agreement with the
literature.17 13C NMR (50 MHz, CDCl3) d 140.0, 126.9,
124.5, 61.6, 38.9. IR (film) 2112 cmK1 (for N3).
8. (a) Gendreau, P. L.; Petitto, J. M.; Schnauss, R.; Frantz, K. J.;
Van Hartesveldt, C.; Gariepy, J. L.; Lewis, M. H. Eur.
J. Pharmacol. 1997, 337, 147–155. (b) Baker, L. E.; Svensson,
K. A.; Garner, K. J.; Goodwin, A. K. Eur. J. Pharmacol. 1998,
358, 101–109. (c) Nilsson, C. L.; Hellstrand, M.; Ekman, A.;
Eriksson, E. Life Sci. 1999, 64, 939–951. (d) Depoortere, R.;
Perrault, G.; Sanger, D. J. Pharmacol. Biochem. Behav. 2000,
65, 31–34. (e) Rogoz, Z.; Klodzinska, A.; Maj, J. Pol.
J. Pharmacol. 2000, 52, 459–462. (f) Christian, A. J.;
Goodwin, A. K.; Baker, L. E. Pharmacol. Biochem. Behav.
2001, 68, 371–377. (g) Goudie, A. J.; Baker, L. E.; Smith,
J. A.; Prus, A. J.; Svensson, K. A.; Cortes-Burgos, L. A.;
Wong, E. H.; Haadsma-Svensson, S. Behav. Pharmacol. 2001,
12, 303–315. (h) Goudie, A. J.; Smith;, J. A.; Millan, M. J.
Psychopharmacology 2004, 171, 212–222.
4.1.15. 2-Aminoindan hydrochloride (23). The hydrogen-
ation procedure described above for 2-azido-5,6-
dimethoxyindan (15) was applied to 2-azidoindan (22) to
give 2-aminoindan hydrochloride (23) in a yield of 95%.
Colorless crystal. MpO237 8C (from MeOH–Et2O, lit.19
decomp. at 220 8C). 1H NMR (200 MHz, D2O) d 7.34–7.22
(AA0BB0 system, m, 4H, Aryl-H), 4.13 (tt, 1H, H-2, JZ7.2,
3.9 Hz), 3.37 (A part of AB system, dd, 2H, JZ16.9,
7.2 Hz), 3.01 (B part of AB system, dd, 2H, JZ16.9,
3.9 Hz). 13C NMR (50 MHz, D2O) d 143.7, 131.9, 129.4,
56.0, 41.7.
¨
9. Goksu, S.; Kazaz, C.; Su¨tbeyaz, Y.; Sec¸en, H. Helv. Chim.
Acta 2003, 86, 3310–3313.
10. (a) Dannenfelser, R. M.; He, H.; Joshi, Y.; Bateman, S.;
Serajuddin, A. T. M. J. Pharm. Sci. 2004, 93, 1165–1175. (b)
Prashad, M.; Hu, B.; Har, D.; Repic, O.; Blacklock, T. J.;
Acemoglu, M. Adv. Synth. Catal. 2001, 343, 461–472. (c)
Ksander, G. M.; deJesus, R.; Yuan, A.; Fink, C.; Moskal, M.;
Carlson, E.; Kukkola, P.; Bilci, N.; Wallace, E.; Neubert, A.;
Feldman, D.; Mogelesky, T.; Poirier, K.; Jeune, M.; Steele, R.;
Wasvery, J.; Stephan, Z.; Cahill, E.; Webb, R.; Navarrete, A.;
Lee, W.; Gibson, J.; Alexander, N.; Sharif, H.; Hospattankar,
A. J. Med. Chem. 2001, 44, 4677–4687.
4.1.16. 2-Amino-5,6-dibromoindan hydrobromide (24).
The literature procedure for the synthesis of 2-amino-5-
bromoindan hydrobromide (20)10b was applied to 2-amino-
indan hydrochloride (23) using 2.5 equiv Br2 to give
2-amino-5,6-dibromoindan hydrobromide (24) in a yield
of 70%. Yellowish crystal. MpO290 8C (from MeOH–
Et2O). 1H NMR (200 MHz, DMSO-d6) d 8.25 (bs, 3H,
NH3Br), 7.71 (bs, 2H, H-4 and H-7), 4.10–4.00 (m, 1H,
H-2), 3.28 (A part of AB system, dd, 2H, JZ17.0, 7.3 Hz),
2.98 (B part of AB system, dd, 2H, JZ17.0, 4.9 Hz). 13C
NMR (50 MHz, DMSO-d6) d 143.8, 131.5, 123.6, 52.4,
11. Lindley, J. Tetrahedron 1984, 40, 1433–1456.
12. (a) Jung, M. E.; Shaw, T. J. J. Am. Chem. Soc. 1980, 102,

¨
S. Goksu, H. Sec¸en / Tetrahedron 61 (2005) 6801–6807
6807
6304–6311. (b) Mete, E.; Maras, A.; Secen, H. Russ. Chem.
Bull. 2003, 52, 1879–1881.
17. Bowers, N. I.; Boyd, D. R.; Sharma, N. D.; Goodrich, P. A.;
Groocock, M. R.; Blacker, A. J.; Goode, P.; Dalton, H.
J. Chem. Soc., Perkin Trans. 1 1999, 1453–1461.
18. For the preparation of HN3 see: Fieser, L. F.; Fieser, M. In
Reagents for Organic Synthesis, Vol. 1; Wiley: New York,
1967; p 446.
13. Romero, A. G.; Leiby, J. A., US Patent, 5,936,000, 1999;
Chem. Abstr. 1999, 131, 144423.
¨
14. (a) Goksu, S.; Sec¸en, H.; Sutbeyaz, Y. Synthesis 2002,
¨
¨
¨
2373–2378. (b) Goksu, S.; Ozalp, C.; Sec¸en, H.; Sutbeyaz,
Y.; Saripinar, E. Synthesis 2004, 2849–2854.
15. Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297–368.
16. Rao, H. S. P.; Siva, P. Synth. Commun. 1994, 24, 549–555.
19. Levin, N.; Graham, B. E.; Kolloff, H. G. J. Org. Chem. 1944,
9, 380–391.