Synthesis of a novel series of benzocycloalkene derivatives as melatonin receptor agonists

Article abstract of DOI:10.1021/jm020114g

We synthesized a novel series of benzocycloalkene derivatives and evaluated their binding affinities to melatonin receptors. To control the spatial position of the amide group, one of the important pharmacophores, we incorporated an endo double bond, an e

Full text of DOI:10.1021/jm020114g

4212
J . Med. Chem. 2002, 45, 4212-4221
Syn th esis of a Novel Ser ies of Ben zocycloa lk en e Der iva tives a s Mela ton in
Recep tor Agon ists
Kohji Fukatsu, Osamu Uchikawa,* Mitsuru Kawada, Toru Yamano, Masayuki Yamashita, Koki Kato,
Keisuke Hirai, Shuji Hinuma, Masaomi Miyamoto, and Shigenori Ohkawa
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 17-85, J usohonmachi 2-chome,
Yodogawa-ku, Osaka 532-8686, J apan
Received March 12, 2002
We synthesized a novel series of benzocycloalkene derivatives and evaluated their binding
affinities to melatonin receptors. To control the spatial position of the amide group, one of the
important pharmacophores, we incorporated an endo double bond, an exo double bond (E- and
Z-configurations), and a chiral center (R- and S-configurations) at position 1. The indan
derivatives with the S-configuration at position 1 were the most promising in terms of potency
and selectivity for the human melatonin receptor (MT1 site), while compounds with the
R-configuration showed little potential. Our next attempt was to investigate the most favorable
conformation of the methoxy group, the other important pharmacophore for binding to the
MT1 receptor. The introduction of a methyl group at position 5 of the indene ring conserved
affinity; however, at position 7, it caused a decrease in affinity. These results suggested that
the substitution at position 7 forced the methoxy group to adopt an unfavorable orientation.
The optimization of the condensed ring size and substituents led to (S)-8d [(S)-N-[2-(2,3-dihydro-
6-methoxy-1H-inden-1-yl)ethyl]propionamide], which had high affinity for the human MT1
receptor (Ki ) 0.041 nM) but no significant affinity for the hamster MT3 receptor (Ki ) 3570
nM). In addition, a practical synthetic method of chiral N-[2-(2,3-dihydro-1H-inden-1-yl)ethyl]-
alkanamides employing asymmetric hydrogenation with (S)-2,2′-bis(diphenylphosphino)-1,1′-
binaphthyl-Ru has been established.
In tr od u ction
quinone reductase 2 (QR2, EC 1.6.99.2), but the physi-
ological function of this enzyme has not been well-
characterized.11 Thus, to avoid unknown potential side
effects, we have investigated compounds that have
affinity for the MT1 receptor but do not affect the MT3.
According to reports on indolic and nonindolic mela-
tonin receptor ligands, several models of the docking
between ligands and receptors have been proposed12 and
a comparative molecular field analysis of melatonin
receptor ligands was investigated.13 These studies and
the structures of the ligands suggested that the pyrrole
unit of melatonin was not essential for receptor binding.
Furthermore, it was also suggested that the amide
group in the side chain and the methoxy group on the
benzene ring were important ligand pharmacophores.
With a view to altering the conformation of the side
chain and the methoxy group, we chose benzocyclo-
alkenes (indan, tetraline, and benzocycloheptene) as
versatile scaffolds and attempted to elevate the affinity
and selectivity for the MT1 receptor.
Structural modifications to the benzocycloalkene de-
rivatives 2 included the introduction of (a) an endo
double bond as in melatonin, (b) an exo double bond
followed by E/Z separation, and (c) a chiral center to
control the spatial positioning of the amide side chain.
Additionally, we modified the substituents on the
benzene ring to clarify the most favorable conformation
for the methoxy group on the benzene ring. These
strategies are illustrated in Figure 1.
Sleep disorders are commonly caused by exposure to
stress, and it was reported that they affect one-third of
Americans.1 Benzodiazepines are normally used for the
treatment of sleep disorders since they have fewer side
effects than barbiturates. However, the administration
of benzodiazepines to the elderly is restricted because
it can cause rebound insomnia,2 muscle relaxation,3 and
amnesia.4 We therefore attempted to develop a new type
of agent for sleep disorders, focusing on the natural
hormone melatonin (1).
The pineal hormone melatonin plays a key role in
modulating circadian and seasonal rhythms.5 A large
number of studies on melatonin for the treatment of
circadian rhythm disorders such as delayed sleep phase
syndrome6 and jet lag7 have been reported. However,
the effect of melatonin is limited by its short half-life
in the human body,8 and the safety of melatonin when
it is administered chronically has yet to be tested.
Melatonin receptors can be classified into MT1, MT2, and
MT3 subtypes, and melatonin is suggested to exert its
regulatory function through MT1 and MT2 receptors.9
The expression of the MT1 receptor mRNA was observed
throughout the human brain, while the expression of
the MT2 receptor mRNA was observed in the retina with
much lower expression in the brain and hippocampus.10
For this reason, it was thought that interaction with
the MT1 receptor was a potential target for the regula-
tion of sleep disorders. Recently, the MT3 binding site
has been identified as a melatonin sensitive form of the
Ch em istr y
Benzocycloalkene derivatives having a 2-amidoethyl
side chain were synthesized according to the general
* To whom correspondence should be addressed. Tel: +81-6-6300-
6546. Fax: +81-6-6300-6306. E-mail: uchikawa_osamu@takeda.co.jp.
10.1021/jm020114g CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/15/2002

Benzocycloalkene Derivatives as Melatonin Agonists
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19 4213
F igu r e 1. Design of benzocycloalkene derivatives (2) for melatonin receptor agonists. The structure shows (a) introduction of an
endo double bond, (b) introduction of an exo double bond followed by E/Z separation, and (c) introduction of a chiral center.
Substitution (R2) on the benzene ring to restrict the conformation of the alkoxy group (OR1). In addition, ring size (n), substituents
(R1, R3, and R4), and the length of the side chain (m) are represented.
Sch em e 1. Synthesis of Benzocycloalkene Derivatives Having a 2-Amidoethyl Side Chaina
a
Reagents: (a) (C2H5O)2P(O)CH2CN, NaH (method A) or CH3CN, LiN(TMS)2 and then p-TsOH/toluene (method B). (b) H2/Raney-Ni,
NH3/C2H5OH (method C). (c) H2/Raney-Co, NH3/C2H5OH (method D). (d) HCl/C2H5OH (method E). (e) R′CO-X, (C2H5)3N (method F) or
R′CO-X, aqueous NaOH (method G). (f) H2/Pd-C (method H).
route outlined in Scheme 1. The starting ketones 3 were
cyanomethylenated employing Horner-Emmons olefi-
nation (method A) or an Aldol type reaction with
acetonitrile followed by dehydration (method B) to afford
4, which could be separated into isomeric pure forms
(E and Z) by column chromatography. Hydrogenation
of 4 using Raney-nickel as a catalyst provided 2-ami-
noethyl derivatives 5 (method C). Raney-cobalt-cata-
lyzed hydrogenation of 4 and selective reduction of the
cyano group14 afforded 2-aminoethylidene derivatives
6 (method D), which could be converted into endo olefins
7 under acidic conditions (method E). The amines 5-7
thus obtained were acylated in the presence of triethy-
lamine (method F) or under Schotten-Baumann condi-
tions (method G) to afford 8-10, respectively. Com-
pound 8 was also obtained by catalytic hydrogenation
of olefins 9 or 10 (method H).
The synthetic routes to the compounds having an
amidomethyl (13) or a 3-amidopropyl side chain (19) are
shown in Scheme 2. Hydrocyanation of ketone 3c using
trimethylsilyl cyanide followed by dehydration afforded
cyanoindene 11 (method I). Hydrogenation of the cyano
group of 11 using Raney-cobalt provided aminomethyl
compound 12, which was trifluoroacetylated and hy-
drogenated to afford 13. Compound 19 was also syn-
thesized from 3c. Horner-Emmons olefination of 3c
followed by hydrogenation gave acetate 14 (method J ),
which was converted into 2-cyanoethyl compound 17
with a three step sequence: lithium aluminum hydride
reduction of the ethoxycarbonyl group (method K),
bromination of the resulting alcohol 15 (method L), and
cyanation using sodium cyanide (method M). Finally,
Raney-nickel-catalyzed hydrogenation of 17 followed by
trifluoroacetylation provided 19.
The modification of the methoxy group at position 6
is summarized in Scheme 3. A methyl ether group of
methoxyindan 8d was cleaved with boron tribromide to
afford phenol 20 (method N), which was alkylated to
yield alkoxy compounds 21a -c (method O).
Hydrazinolysis of chiral acetamide (S)-8c, which was
obtained by optical resolution utilizing chiral high-
performance liquid chromatography (HPLC) (method P),
gave chiral amine (S)-5c (method Q) (Scheme 4). Abso-
lute stereochemistry was determined by X-ray crystal-
lographic analysis of p-bromobenzamide (S)-8o, which
was prepared from (S)-5c. Compound (S)-5c was acy-
lated to give chiral amides (S)-8d , (S)-8e, and (S)-8h .
The corresponding R-isomers ((R)-8d , (R)-8e, and (R)-
8h ) were obtained in the same manner.
To obtain chiral compounds on a large scale, we
planned to establish a practical method using asym-
metric hydrogenation. There have been only a few
reports on the asymmetric hydrogenation of (amido-
methyl)olefins, and these substrates contained allylic

4214 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19
Fukatsu et al.
Sch em e 2. Synthesis of Benzocycloalkene Derivatives Having Amidomethyl or a 3-Amidopropyl Side Chaina
a
Reagents: (a) TMSCN, ZnI2 and then CF3COOH/toluene (method I). (b) H2/Raney-Co, NH3/C2H5OH (method D). (c) (CF3CO)2O, (C2H5)3N
(method F). (d) H2/Pd-C (method H). (e) (C2H5O)2P(O)CH2COOC2H5, NaH and then H2/Pd-C (method J ). (f) LiAlH4 (method K). (g) PBr3
(method L). (h) NaCN (method M). (i) H2/Raney-Ni, NH3/C2H5OH (method C).
Sch em e 3. Modification of the Alkoxy Groupa
a
Reagents: (a) BBr3 (method N). (b) R-X, K2CO3 (method O).
Sch em e 4. Synthesis of the Chiral Compoundsa
a
Reagents: (a) NH2NH2‚H2O and then HCl (method Q). (b) RCO-X (method F or G).
alcohol or unsaturated carboxylic acid to improve the
efficiency of enantioselective hydrogenation.15 We at-
tempted to apply readily available Ru(OAc)2[(S)-2,2′-bis-
(diphenylphosphino)-1,1′-binaphthyl (binap)] to indan
derivatives (E)-9a , (Z)-9a , and 10a (Table 1). We have
found that hydrogenation of E-olefin (E)-9a successfully
afforded (S)-8d having the S-configuration in 98% yield
with 95% ee, and optically pure (S)-8d was isolated in
83% yield (method R). In contrast, Z-olefin (Z)-9a was
hydrogenated to yield the corresponding R-isomer (R)-
8d in 95% yield with 80% ee. These exo olefins were
versatile materials for the synthesis of chiral N-[2-(2,3-
dihydro-1H-inden-1-yl)ethyl]alkanamides. However, hy-
drogenation of 10a having an endo double bond afforded
(S)-8d with an unsatisfactory enatioselectivity. All of
the synthesized compounds are listed in Table 2.
Biologica l Resu lts a n d Discu ssion
Affinities for the MT1 receptor were evaluated for the
competition of 2-[125I]iodomelatonin with human mela-
tonin receptors expressed in Chinese hamster ovary
(CHO) cells, and affinities for the MT3 receptor were
evaluated with Syrian hamster brain and peripheral
organs. The Ki values of the compounds tested are listed
in Table 3. Evaluation of melatonin revealed that it
competes with 2-[125I]iodomelatonin to bind the MT1
receptor with a Ki value of 0.082 nM and also the MT3
receptor with a Ki value of 28 nM.
Because the amide moiety of melatonin was consid-
ered to be an important hydrogen bond donor and
acceptor for interaction with the MT1 receptor, we
attempted to change the spatial conformation of the
amide group to potentiate the affinity for the MT1

Benzocycloalkene Derivatives as Melatonin Agonists
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19 4215
Ta ble 1. Asymmetric Hydrogenation of Olefins 9a and 10a Using (S)-binap as a Chiral Auxiliary
receptor and to elevate MT1/MT3 selectivity. Initially,
we introduced an exo (E, Z) or endo double bond to
restrict the conformation of the side chain. A comparison
of the E- and Z-configurations of the exo double bond
revealed the indan derivative (E)-9a having the E-
configuration to show higher affinity for the MT1 recep-
tor than (Z)-9a . Moving the amide group toward the
benzene ring seemed to attenuate the affinity for the
MT1 receptor. On comparison between the exo and the
endo double bond, endo compound 10a was found to
exhibit higher affinity for the MT1 receptor than (E)-
9a . Notably, the 2-phenyindene derivative 10c had the
highest affinity for the MT1 receptor. In the structure-
activity relationships of melatonin derivatives, a similar
effect of substitution of the phenyl group at position 2
was reported. However, introduction of the benzyl group
at position 2 of the indene ring (10d ) reduced affinity
for the MT1 receptor.
We also attempted to reduce the double bond and
separate the resulting enantiomers. Although a marked
difference was not observed on reduction of the double
bond of 10a ,b (8d ,h ), reduction of 10c attenuated the
affinity for the MT1 receptor (8m ). However, these
enantiomers were the most promising. In the MT1
binding assay, the compounds possessing the S-config-
uration ((S)-8c, (S)-8d , (S)-8e, and (S)-8h ) had more
than 100-fold the affinity of the corresponding R-isomers
((R)-8c, (R)-8d , (R)-8e, and (R)-8h ), and the S-isomers
showed less affinity for the MT3 receptor than the
R-isomers. The MT1/MT3 selectivity of S-isomers over-
whelmed that of the compounds having an endo double
bond, 10a -d , and melatonin.
methyl group at position 5 of the indan nucleus (8j)
showed a higher affinity than the compound having a
methyl group at position 7 (8i). In a homology modeling
study based on the structure of Bacterio rhodopsine, it
was suggested that His195 in helix five forms a hydrogen
bond with a methoxy oxygen in melatonin, and the
methyl group on the oxygen points toward position 4 of
melatonin.12a In order for a hydrogen bond to form
between the histidine residue and the methoxy oxygen
of benzocycloalkene derivatives, the direction of the
methyl group on the oxygen should be restricted. The
methyl group at position 7 of the indan nucleus orients
the methyl group on the oxygen toward position 5 by
steric repulsion and orients oxygen lone pairs toward
position 7 (Figure 2B). In contrast, the methyl group at
position 5 settles lone pairs of the methoxy oxygen in
the appropriate conformation for interaction with the
MT1 receptor (Figure 2A). The same explanation might
be applied to dimethoxy compounds 8k ,l.16
Additionally, the effect of changing the size of the
annelating ring was examined. The affinity for the MT1
receptor of the compound having a five-membered ring
(8h ) was almost 2-fold that of the compound having a
six-membered ring (8b). The compound having a seven-
membered ring (8a ) had markedly decreased affinity (8a
vs 8h ).17 Chain extension of the amide alkyl group
increased the affinity of the ethyl (propionamide 8d ) and
propyl (butyramide 8e) group. In contrast, incorporation
of the branched alkyl group (8g) reduced affinity.
Incorporation of a halogen atom into the amide alkyl
group (trifluoroacetamide 8h ) increased affinity in
comparison with acetamide 8c.
The methoxy group of melatonin was defined as
another important pharmacophore.12 To clarify the most
favorable conformation of the methoxy group in our
series, a methyl group was introduced at the ortho
position of the methoxy group. The compound having a
Changing the length of the side chain as the spacer
greatly influenced the affinity. 3-Amidopropyl derivative
19 had about 20-fold less affinity than 2-amidoethyl
derivative 8h , and the amidomethyl side chain (13)
markedly reduced affinity in comparison with the

4216 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19
Fukatsu et al.
Ta ble 2. Method of Preparation and Intermediates of Benzocycloalkene Derivatives
method of
no.a
8a
8b
8c
(S)-8c
(R)-8c
8d
(S)-8d
(R)-8d
8e
(S)-8e
(R)-8e
8f
8g
8h
(S)-8h
(R)-8h
8i
8j
8k
8l
8m
R1
CH3O
CH3O
CH3O
R2
R3
R4
n
m
preparationb
intermediatesc
H
H
H
H
H
H
CF3
CF3
CH3
3
2
1
1
1
1
A, D, F, H
A, D, F, H
A, C, G
P
3a , 4a , (E)-6a , (E)-9c
3b, 4b, 6b, (E)-9b
3c, (E)-4c, 5c
8c
P
8c
CH3O
CH3O
H
H
H
H
C2H5
1
1
1
1
A, C, G
Q, G, or R
Q, G
A, C, G
Q, G
3c, (E)-4c, 5c
(S)-8c, (S)-5c, or (E)-9a
(R)-8c, (R)-5c
3c, (E)-4c, 5c
(S)-8c, (S)-5c
(R)-8c, (R)-5c
3c, (E)-4c, 5c
3c, (E)-4c, 5c
3c, (E)-4c, 5c
(S)-8c, (S)-5c
(R)-8c, (R)-5c
3d , (E)-4d , (E)-6d , (E)-9d
3e, (E)-4e, (E)-6e, (E)-9e
3f, (E)-4f, (E)-6f, 5f
3g, 4g, 5g
(CH2)2CH3
Q, G
CH3O
CH3O
CH3O
H
H
H
H
H
H
(CH2)3CH3
CH(CH3)2
CF3
1
1
1
1
1
1
A, C, F
A, C, G
A, C, F
Q, F
Q, F
CH3O
CH3O
CH3O
CH3O
CH3O
H
7-CH3
5-CH3
7-CH3O
5-CH3O
H
H
H
H
H
CF3
CF3
CH3
CH3
CF3
CF3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
A, D, F, H
A, D, F, H
A, D, G, H
A, C, F
H
C6H5
H
10c
8n
H
H
A, D, F, H
Q, G
3h , 4h , (E)-6h , (E)-9h
(S)-8c, (S)-5c
3c, (E)-4c, (E)-6c
3c, (Z)-4c, (Z)-6c
3c, (E)-4c, (E)-6c, 7c
3c, (E)-4c, (E)-6c, 7c
3i, (E)- 4i, 7i
3j, 4j, 6j, 7j
(S)-8o
(E)-9a
(Z)-9a
10a
10b
10c
10d
13
19
20
21a
21b
21c
CH3O
H
C6H4-4-Br
C2H5
C2H5
C2H5
CF3
A, D, F
A, D, F
A, D, E, F
A, D, E, F
B, D, F
B, D, E, F
I, D, F, H
J , K, L, M, C, F
N
H
H
C6H5
CH2C6H5
CF3
CF3
CF3
CF3
CH3O
CH3O
HO
C2H5O
CH3(CH2)2O
(CH3)2CHO
H
H
H
H
H
H
H
H
H
H
H
H
1
1
1
1
1
1
0
2
1
1
1
1
3c, 11, 12
3c, 14-18
C2H5
C2H5
C2H5
C2H5
8d
20
20
20
O
O
O
a
b
All of the target compounds listed in the table were analyzed correctly ((0.4%) for C, H, and N. A combination of methods. c The
chemical names of intermediates are given in the Experimental Section.
F igu r e 2. Schematic models of interaction between the indan derivatives and the histidine residue of the MT1 receptor. Compound
8j (A) exhibited higher affinity than 8i (B).
2-amidoethyl side chain (8h ). Replacing the methoxy
group with an ethoxy (21a ), a propoxy (21b), and an
isopropoxy (21c) group led to a decrease in affinity.18
The contribution of the methoxy group was also dem-
onstrated by the weak activity seen with hydroxy (20)
and deoxy (8n ).
Con clu sion
We designed and synthesized a novel series of ben-
zocycloalkene derivatives focusing on the conformation
of the amide side chain and the methoxy group. In
receptor binding assays, it was revealed that indan

Benzocycloalkene Derivatives as Melatonin Agonists
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19 4217
Ta ble 3. Affinities of Benzocycloalkene Derivatives for Human
Melatonin Receptor (MT1 Site) and Syrian Hamster Brain
Melatonin Receptor (MT3 Site)
Exp er im en ta l Section
Melting points were determined on a Yanagimoto mi-
cromelting point apparatus and are uncorrected. 1H NMR
spectra were recorded on a Varian Gemini-200 spectrometer
(200 MHz), with tetramethylsilane as the internal standard.
Optical rotations were determined with a J ASCO DIP-370
digital polarimeter. Thin-layer chromatography (TLC) analyses
were carried out on Merck Kieselgel 60 F254 plates. Elemental
analyses of the target compounds were carried out by Takeda
Analytical Research Laboratories, Ltd. Tetrahydrofuran (THF)
was distilled over calcium hydride prior to use, and other
solvents and reagents were used without purification. The
Raney-cobalt used was commercially available as ODHT-60
(Kawaken Finechemical Co. Ltd.), and was washed with
distilled water (three times) and EtOH (once) prior to use.
Solutions in organic solvents were dried over anhydrous
MgSO4, and concentration of the organic solution was carried
out under reduced pressure. Chromatographic purification was
carried out on silica gel columns (Merck Kieselgel 60, 0.063-
0.200 mm). Yields were not maximized.
Met h od A. (E)-(2,3-Dih yd r o-6-m et h oxy-1H -in d en -1-
ylid en e)a cet on it r ile ((E)-4c) a n d (Z)-(2,3-Dih yd r o-6-
m eth oxy-1H-in d en -1-ylid en e)a ceton itr ile ((Z)-4c). To a
solution of diethyl cyanomethylphosphonate (9.4 g, 53 mmol)
in THF (60 mL) was added 66% NaH (1.9 g, 53 mmol;
dispersion in oil), and the mixture was cooled in an ice-water
bath before it was stirred at room temperature for 30 min.
After the mixture was cooled again in an ice-water bath, a
suspension of 2,3-dihydro-6-methoxy-1H-inden-1-one (3c) (7.9
g, 48 mmol) in THF (40 mL) was added with stirring, and the
stirring was continued at room temperature for 1 h. The
reaction mixture was poured into water and extracted with
EtOAc. The extract was washed with water and brine, dried,
and concentrated. The residue was crystallized from EtOAc-
hexane, and the solid was collected by filtration to yield 4.9 g
(55% yield) of (E)-4c; mp 95-96 °C. 1H NMR (CDCl3): δ 3.01-
3.18 (m, 4H), 3.83 (s, 3H), 5.61 (t, 1H, J ) 2.4 Hz), 6.96-7.03
(m, 2H), 7.27 (d, 1H, J ) 8.8 Hz). The filtrate was concentrated,
and the residue was purified by column chromatography
(hexane:EtOAc 23:2) to afford 1.3 g (15% yield) of (Z)-4c; mp
receptor bindinga
no.
MT1,b Ki (nM)
MT3,c Ki (nM)
melatonin
8a
8b
0.0823 ( 0.0021
1.65 ( 0.49
0.0469 ( 0.0125
0.131 ( 0.038
0.0733 ( 0.0201
10.6 ( 0.5
0.0728 ( 0.0186
0.0410 ( 0.0102
30.1 ( 3.2
27.6 ( 0.3
>10 000
608 ( 372
316 ( 166
4180 ( 118
372 ( 35
8c
(S)-8c
(R)-8c
8d
(S)-8d
(R)-8d
8e
(S)-8e
(R)-8e
8f
8g
8h
(S)-8h
(R)-8h
8i
686 ( 202
3570 ( 760
561 ( 161
946 ( 301
2230 ( 248
785 ( 207
837 ( 489
2270 ( 813
497 ( 205
1550 ( 387
374 ( 83
0.0553 ( 0.0054
0.0321 ( 0.0064
43.7 ( 10.3
1.32 ( 0.32
0.250 ( 0.041
0.0225 ( 0.0059
0.0123 ( 0.0033
6.43 ( 0.34
28.5 ( 1.9
2600 ( 687
4580 ( 1480
3150 ( 1050
782 ( 237
1770 ( 442
>10 000
8j
8k
8l
8m
0.0984 ( 0.0096
46.7 ( 9.3
4.09 ( 0.79
1.60 ( 0.18
8n
12.3 ( 3.4
(E)-9a
(Z)-9a
10a
10b
10c
10d
13
19
20
21a
21b
21c
0.208 ( 0.021
0.927 ( 0.336
0.0231 ( 0.0041
0.0408 ( 0.0098
0.006 02 ( 0.000 52
6.84 ( 1.80
1190 ( 439
467 ( 128
48.6 ( 8.7
9.09 ( 2.90
48.0 ( 17.7
2450 ( 948
428 ( 125
353 ( 147
1810 ( 54
760 ( 238
812 ( 121
5490 ( 1390
28.6 ( 8.0
0.526 ( 0.136
23.8 ( 3.4
0.100 ( 0.029
0.425 ( 0.066
1.45 ( 0.23
1
68-69 °C (EtOAc-hexane). H NMR (CDCl3): δ 2.97 (s, 4H),
a
The Ki values were calculated from IC50 values. IC50 values
were obtained from the molar concentration of test compound
required to inhibit by 50% the 2-[125I]iodomelatonin specific
3.86 (s, 3H), 5.31 (s, 1H), 7.00 (dd, 1H, J ) 2.6 Hz, 8.4 Hz),
7.24 (d, 1H, J ) 8.4 Hz), 7.86 (d, 1H, J ) 2.6 Hz). Further
elution afforded 1.7 g (18% yield) of (E)-4c. With a similar
procedure, the following compounds were prepared (6,7,8,9-
tetrahydro-3-methoxy-5H-benzocyclohepten-5-ylidene)acetoni-
trile (4a ), (3,4-dihydro-7-methoxy-1(2H)-naphthalenylidene)-
acetonitrile (4b), (E)-(5-bromo-2,3-dihydro-6-methoxy-7-methyl-
1H-inden-1-ylidene)acetonitrile ((E)-4d ), (E)-(7-bromo-2,3-
dihydro-6-methoxy-5-methyl-1H-inden-1-ylidene)acetonitrile
((E)-4e), (E)-(2,3-dihydro-6,7-dimethoxy-1H-inden-1-ylidene)-
acetonitrile ((E)-4f), (2,3-dihydro-5,6-dimethoxy-1H-inden-1-
ylidene)acetonitrile (4g), and (2,3-dihydro-1H-inden-1-ylidene)-
acetonitrile (4h ).
b
binding. Human melatonin receptor expressed in CHO cells.
c Syrian hamster brain and peripheral organs and were calculated
by log-probit analysis.
derivatives having an S-configuration at position 1
showed greater affinity for the MT1 receptor than
compounds with the R-configuration or with a double
bond (endo, exo). Because the S-compounds, e.g., (S)-
8d , exhibited little affinity for the MT3 receptor, the
S-configured chiral center in benzocycloalkene deriva-
tives was significant on account of the selectivity toward
the MT1 receptor.19 To obtain S-compounds practically,
we examined the asymmetric synthesis of (S)-8d . We
clarified that hydrogenation of (E)-9a with an exo E
double bond using Ru(OAc)2[(S)-binap] as a catalyst
gave (S)-8d conveniently and efficiently.
It was also revealed that the conformation of the
methoxy group of indan derivatives, in relation to the
orientation of oxygen lone pairs, is important for affin-
ity. The chiral indan derivatives reported herein exhib-
ited no significant affinity for other receptors and
enzymes and exhibited agonistic activity toward mela-
tonin receptors in experiments on forskolin-induced
adenosine cyclic 3′,5′-phosphate (cAMP) production in
CHO cells expressing the human MT1 receptor (see the
Supporting Information). These results would be a basis
for further investigation.
Meth od B. (E)-(2,3-Dih yd r o-6-m eth oxy-2-p h en yl-1H-
in d en -1-ylid en e)a cet on it r ile ((E)-4i). To a solution of
1,1,1,3,3,3-hexamethyldisilazane (2.9 mL, 14 mmol) in THF
(80 mL) was added dropwise 1.6 M n-BuLi hexane solution
(8.7 mL, 14 mmol) at -78 °C under an argon atmosphere, and
the mixture was stirred for 15 min. To the mixture was added
dropwise acetonitrile (0.65 mL, 12 mmol), and stirring was
continued for 20 min; then, a solution of 2,3-dihydro-6-
methoxy-2-phenyl-1H-inden-1-one (3i)20 (2.7 g, 11 mmol) in
THF (30 mL) was added dropwise. After the reaction mixture
was stirred for 1 h, water was added and the mixture was
allowed to warm to room temperature and extracted with
EtOAc. The extract was washed with water and brine, dried,
and concentrated. The residue was dissolved in toluene (100
mL), and 10-camphorsulfonic acid (0.50 g) was added to the
resulting solution. The mixture was stirred under reflux with
an azeotropic water-removing system for 1 h. After the reaction
mixture was cooled, water was added and the mixture was
extracted with EtOAc. The extract was washed with water and
brine, dried, and concentrated. The residue was crystallized

4218 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19
Fukatsu et al.
from EtOAc-diisopropyl ether to recover 1.0 g of the starting
material 3i. The mother liquid was concentrated, and the
residue was again crystallized from EtOAc-diisopropyl ether
to afford 0.47 g (16% yield) of (E)-4i; mp 112-114 °C. 1H NMR
(CDCl3): δ 3.03 (d, 1H, J ) 17.0 Hz), 3.59 (dd, 1H, J ) 8.2 Hz,
17.0 Hz), 3.86 (s, 3H), 4.49 (d, 1H, J ) 8.2 Hz), 5.69 (d, 1H, J
) 2.6 Hz), 6.95-7.32 (m, 8H). By a similar procedure, [2,3-
dihydro-6-methoxy-2-(phenylmethyl)-1H-inden-1-ylidene]ace-
tonitrile (4j) was prepared.
was washed with water and brine, dried, and concentrated.
The residue was purified by column chromatography (EtOAc)
followed by recrystallization with EtOAc to afford 2.3 g (59%
1
yield) of (E)-9a ; mp 129-131 °C. H NMR (CDCl3): δ 1.18 (t,
3H, J ) 7.5 Hz), 2.24 (q, 2H, J ) 7.5 Hz), 2.73-2.86 (m, 2H),
2.90-3.00 (m, 2H), 3.81 (s, 3H), 4.04 (t, 2H, J ) 6.2 Hz), 5.55
(br s, 1H), 5.88 (m, 1H), 6.79 (dd, 1H, J ) 2.4 Hz, 8.1 Hz),
6.93 (d, 1H, J ) 2.4 Hz), 7.14 (d, 1H, J ) 8.1 Hz). Anal. (C15H19
-
NO2) C, H, N. A similar procedure was used to prepare the
following compounds: N-[2-(2,3-dihydro-6-methoxy-1H-inden-
1-yl)ethyl]pentanamide (8f), N-[2-(2,3-dihydro-6-methoxy-1H-
inden-1-yl)ethyl]-2,2,2-trifluoroacetamide (8h ), (S)-N-[2-(2,3-
dihydro-6-methoxy-1H-inden-1-yl)ethyl]-2,2,2-trifluoroacet-
amide ((S)-8h ), (R)-N-[2-(2,3-dihydro-6-methoxy-1H-inden-1-
yl)ethyl]-2,2,2-trifluoroacetamide ((R)-8h ), N-[2-(2,3-dihydro-
6,7-dimethoxy-1H-inden-1-yl)ethyl]acetamide (8k ), N-[2-(2,3-
dihydro-5,6-dimethoxy-1H-inden-1-yl)ethyl]acetamide (8l),
(Z)-N-[2-(2,3-dihydro-6-methoxy-1H-inden-1-ylidene)ethyl]pro-
pionamide ((Z)-9a ), (E)-N-[2-(3,4-dihydro-7-methoxy-1(2H)-
naphthalenylidene)ethyl]-2,2,2-trifluoroacetamide ((E)-9b ),
(E)-2,2,2-trifluoro-N-[2-(6,7,8,9-tetrahydro-3-methoxy-5H-ben-
zocyclohepten-5-ylidene)ethyl]acetamide ((E)-9c), (E)-N-[2-(5-
bromo-2,3-dihydro-6-methoxy-7-methyl-1H-inden-1-ylidene)-
ethyl]-2,2,2-trifluoroacetamide ((E)-9d ), (E)-N-[2-(7-bromo-2,3-
dihydro-6-methoxy-5-methyl-1H-inden-1-ylidene)ethyl]-2,2,2-
trifluoroacetamide ((E)-9e), (E)-N-[2-(2,3-dihydro-1H-inden-1-
ylidene)ethyl]-2,2,2-trifluoroacetamide ((E)-9h ), N-[2-(5-methoxy-
1H-inden-3-yl)ethyl]propionamide (10a ), 2,2,2-trifluoro-N-[2-
(5-methoxy-1H-inden-3-yl)ethyl]acetamide (10b), 2,2,2-trifluoro-
N-[2-(5-methoxy-2-phenyl-1H-inden-3-yl)ethyl]acetamide (10c),
2,2,2-trifluoro-N-[2-[5-methoxy-2-(phenylmethyl)-1H-inden-3-
yl]ethyl]acetamide (10d ), N-[(2,3-dihydro-6-methoxy-1H-inden-
1-yl)methyl]-2,2,2-trifluoroacetamide (13), and N-[3-(2,3-
dihydro-6-methoxy-1H-inden-1-yl)propyl]-2,2,2-trifluoroacet-
amide (19).
Meth od C. 2,3-Dih yd r o-6-m eth oxy-1H-in d en -1-eth a -
n a m in e (5c) a n d 5c Hyd r och lor id e. To a solution of (E)-4c
(4.0 g, 22 mmol) in EtOH (80 mL) were added Raney-nickel
(4.0 g; W2) and 4 M NH3/EtOH (40 mL), and the mixture was
stirred under a hydrogen atmosphere (0.4 MPa) at room
temperature for 5 h. The reaction mixture was filtered, and
the filtrate was concentrated. The residue was purified by
column chromatography (CHCl3:MeOH 97:3, followed by CHCl3:
MeOH:Et3N 90:7:3) to afford 3.3 g (80% yield) of 5c as an oily
product. 1H NMR (CDCl3): δ 1.50-1.76 (m, 2H), 1.90-2.08
(m, 1H), 1.22-1.34 (m, 1H), 2.65-3.20 (m, 5H), 3.79 (s, 3H),
6.71 (dd, 1H, J ) 2.6 Hz, 8.2 Hz), 6.76 (1H, br s), 7.12 (d, 1H,
J ) 8.2 Hz), hidden (2H). Hydrochloride of 5c was prepared
from 5c and 4 M HCl/EtOH and recrystallized from EtOH-
1
diethyl ether; mp 147-148 °C. H NMR (DMSO-d6): δ 1.57-
1.88 (m, 2H), 2.01-2.36 (m, 2H), 2.62-2.92 (m, 4H), 3.07-
3.23 (m, 1H), 3.73 (s, 3H), 6.68-6.78 (m, 2H), 7.12 (d, 1H, J )
8.2 Hz), 8.14 (br s, 2H). A similar procedure was employed to
prepare the following compounds: 2,3-dihydro-5,6-dimethoxy-
1H-inden-1-ethanamine hydrochloride (5g) and 2,3-dihydro-
6-methoxy-1H-indene-1-propanamine (18).
Meth od D. (E)-2-(2,3-Dih yd r o-6-m eth oxy-1H-in d en -1-
ylid en e)eth a n a m in e ((E)-6c). To a solution of (E)-4c (2.0 g,
11 mmol) in EtOH (20 mL) were added Raney-cobalt (2.0 g)
and 4 M NH3/EtOH (10 mL), and the mixture was stirred
under a hydrogen atmosphere (0.4 MPa) at 40 °C for 6 h. The
mixture was filtered, and the filtrate was concentrated to
Meth od G. N-[2-(2,3-Dih yd r o-6-m eth oxy-1H-in d en -1-
yl)eth yl]a ceta m id e (8c). To a suspension of 5c hydrochloride
(16 g, 71 mmol) in THF (100 mL) was added 1 M aqueous
NaOH (180 mL) in an ice-water bath followed by acetic
anhydride (8.7 g, 85 mmol) with vigorous stirring. After it was
stirred for 15 min, the reaction mixture was extracted with
EtOAc. The extract was washed with brine, dried, and
concentrated. The residue was recrystallized from EtOAc-
hexane to yield 16 g (94% yield) of 8c; mp 80-81 °C. 1H NMR
(CDCl3): δ 1.50-1.80 (m, 2H), 1.98 (s, 3H), 1.99-2.14 (m, 1H),
2.21-2.40 (m, 1H), 2.66-2.94 (m, 2H), 3.03-3.17 (m, 1H), 3.38
(dd, 2H, J ) 7.4 Hz, 13.2 Hz), 3.78 (s, 3H), 5.53 (br s, 1H),
1
afford 2.0 g (96% yield) of (E)-6c as an oily product. H NMR
(CDCl3) δ 1.38 (br s, 2H), 2.70-2.80 (m, 2H), 2.89-2.98 (m,
2H), 3.48 (d, 2H, J ) 7.0 Hz), 3.81 (s, 3H), 5.92-6.01 (m, 1H),
6.78 (dd, 1H, J ) 2.4 Hz, 8.2 Hz), 6.97 (d, 1H, J ) 2.4 Hz),
7.14 (d, 1H, J ) 8.2 Hz). A similar procedure was used to
prepare the following compounds: (E)-2-(6,7,8,9-tetrahydro-
3-methoxy-5H-benzocyclohepten-5-ylidene)ethanamine ((E)-
6a ), 2-(3,4-dihydro-7-methoxy-1(2H)-naphthalenylidene)eth-
anamine (6b ), (Z)-2-(2,3-dihydro-6-methoxy-1H-inden-1-yli-
dene)ethanamine ((Z)-6c), (E)-2-(5-bromo-2,3-dihydro-6-meth-
oxy-7-methyl-1H-inden-1-ylidene)ethanamine ((E)-6d ), (E)-2-
(7-bromo-2,3-dihydro-6-methoxy-5-methyl-1H-inden-1-ylidene)-
ethanamine ((E)-6e), (E)-2-(2,3-dihydro-6,7-dimethoxy-1H-
inden-1-ylidene)ethanamine ((E)-6f), (E)-2-(2,3-dihydro-1H-
inden-1-ylidene)ethanamine ((E)-6h ), 2-[2,3-dihydro-6-methoxy-
2-(phenylmethyl)-1H-inden-1-ylidene]ethanamine (6j), 5-meth-
oxy-2-phenyl-1H-inden-3-ethanamine hydrochloride (7i), and
2,3-dihydro-6-methoxy-1H-indene-1-methanamine (12).
6.68-6.75 (m, 2H), 7.11 (d, 1H, J ) 8.0 Hz). Anal. (C14H19
-
NO2) C, H, N. A similar procedure was used to prepare the
following compounds: N-[2-(2,3-dihydro-6-methoxy-1H-inden-
1-yl)ethyl]propionamide (8d ), (S)-N-[2-(2,3-dihydro-6-methoxy-
1H-inden-1-yl)ethyl]propionamide ((S)-8d), (R)-N-[2-(2,3-dihydro-
6-methoxy-1H-inden-1-yl)ethyl]propionamide ((R)-8d ), N-[2-
(2,3-dihydro-6-methoxy-1H-inden-1-yl)ethyl]butanamide (8e),
(S)-N-[2-(2,3-dihydro-6-methoxy-1H-inden-1-yl)ethyl]butana-
mide ((S)-8e), (R)-N-[2-(2,3-dihydro-6-methoxy-1H-inden-1-yl)-
ethyl]butanamide ((R)-8e), N-[2-(2,3-dihydro-6-methoxy-1H-
inden-1-yl)ethyl]-2-methylpropionamide (8g), and (S)-4-bromo-
N-[2-(2,3-dihydro-6-methoxy-1H-inden-1-yl)ethyl]benzamide ((S)-
8o).
Meth od E. 5-Meth oxy-2-(p h en ylm eth yl)-1H-in d en -3-
eth a n a m in e Hyd r och lor id e (7j). A solution of 6j (6.4 g, 23
mmol) in 4 M HCl/EtOH (60 mL) was stirred at 70 °C for 13
h. After the reaction mixture was cooled, the deposited powder
was collected by filtration, washed with diethyl ether, and
dried to afford 1.8 g (24% yield) of 7j. The filtrate was
concentrated, and the residue was crystallized from EtOH-
diethyl ether to afford 3.6 g (50% yield) of 7j; mp 217-219 °C
Meth od H. 2,2,2-Tr iflu or o-N-[2-(6,7,8,9-tetr a h yd r o-3-
m eth oxy-5H-ben zocycloh epten -5-yl)eth yl]acetam ide (8a).
To a solution of (E)-9c (1.5 g, 4.8 mmol) was added 5% Pd-C
(0.40 g, water 50%), and the mixture was stirred under a
hydrogen atmosphere (normal pressure) until the theoretical
amount of hydrogen gas was consumed. The reaction mixture
was filtered, and the filtrate was concentrated. The residue
was recrystallized from diisopropyl ether-hexane to afford 1.5
1
(EtOH). H NMR (DMSO-d6): δ 2.96 (br s, 4H), 3.15 (s, 2H),
3.79 (s, 3H), 3.82 (s, 2H), 6.68 (dd, 1H, J ) 2.2 Hz, 8.1 Hz),
7.06 (d, 1H, J ) 2.2 Hz), 7.15-7.40 (m, 6H), 8.13 (br s, 2H).
By a similar procedure, 5-methoxy-1H-inden-3-ethanamine
(7c) was prepared.
Meth od F . (E)-N-[2-(2,3-Dih yd r o-6-m eth oxy-1H-in d en -
1-ylid en e)eth yl]p r op ion a m id e ((E)-9a ). To a stirring solu-
tion of (E)-6c (3.0 g, 16 mmol) and triethylamine (2.4 g, 24
mmol) in THF (35 mL) was added dropwise propionyl chloride
(1.9 g, 21 mmol) in an ice-water bath, and the stirring was
continued for 15 min. The reaction mixture was poured into
water, and the mixture was extracted with EtOAc. The extract
1
g (97% yield) of 8a ; mp 77-78 °C. H NMR (CDCl3): δ 1.65-
1.96 (m, 7H), 2.08-2.25 (m, 1H), 2.72-2.89 (m, 3H), 3.22-
3.38 (m, 1H), 3.40-3.60 (m, 1H), 3.78 (s, 3H), 6.18 (br s, 1H),
6.61-6.68 (m, 2H), 7.02 (t, 1H, J ) 8.0 Hz). Anal. (C16H20F3-
NO2) C, H, N. A similar procedure was employed to prepare
the following compounds: 2,2,2-trifluoro-N-[2-(1,2,3,4-tetrahy-

Benzocycloalkene Derivatives as Melatonin Agonists
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19 4219
dro-7-methoxy-1-naphthalenyl)ethyl]acetamide (8b), 2,3-dihy-
dro-6,7-dimethoxy-1H-inden-1-ethanamine (5f), N-[2-(2,3-
dihydro-6-methoxy-7-methyl-1H-inden-1-yl)ethyl]-2,2,2-tri-
fluoroacetamide (8i), N-[2-(2,3-dihydro-6-methoxy-5-methyl-
1H-inden-1-yl)ethyl]-2,2,2-trifluoroacetamide (8j), N-[2-(2,3-
dihydro-6-methoxy-2-phenyl-1H-inden-1-yl)ethyl]-2,2,2-triflu-
oroacetamide (8m ), and N-[2-(2,3-dihydro-1H-inden-1-yl)ethyl]-
2,2,2-trifluoroacetamide (8n ).
with EtOAc. The extract was washed with water and brine,
dried, and concentrated. The residue was purified by column
chromatography (hexane:EtOAc 85:15) to afford 1.3 g (93%
yield) of 17 as an oily product. H NMR (CDCl3): δ 1.62-1.89
(m, 2H), 2.03-2.48 (m, 4H), 2.71-2.96 (m, 2H), 3.18-3.33 (m,
1H), 3.80 (s, 3H), 6.72-6.78 (m, 2H), 7.13 (d, 1H, J ) 9.0 Hz).
1
Meth od N. N-[2-(2,3-Dih yd r o-6-h yd r oxy-1H-in d en -1-
yl)eth yl]p r op ion a m id e (20). To a stirring solution of 8d (5.6
g, 22 mmol) in CH2Cl2 (200 mL) was added dropwise boron
tribromide (11 g, 45 mmol) in an ice-water bath, and the
stirring was continued for 2 h. The reaction mixture was
poured into ice-water, and the mixture was stirred at room
temperature for 15 h and then extracted with EtOAc. The
extract was concentrated, and the residue was purified by
column chromatography (EtOAc:MeOH 95:5) and recrystal-
lized from EtOAc-hexane to afford 5.2 g (quantitative yield)
of 20; mp 119-121 °C. 1H NMR (CDCl3): δ 1.15 (t, 3H, J )
7.6 Hz), 1.50-1.80 (m, 2H), 1.87-2.10 (m, 1H), 2.22 (q, 1H, J
) 7.6 Hz), 2.20-2.38 (m, 1H), 2.65-2.90 (m, 2H), 2.97-3.15
(m, 1H), 3.38 (q, 2H, J ) 7.0 Hz), 5.67 (br s, 1H), 6.68 (dd, 1H,
J ) 2.9 Hz, 8.0 Hz), 6.74 (d, 1H, J ) 2.9 Hz), 7.05 (d, 1H, J )
8.0 Hz). Anal. (C14H19NO2) C, H, N.
Meth od I. 5-Meth oxy-1H-in d en e-3-ca r bon itr ile (11). To
a solution of 3c (10 g, 62 mmol) and ZnI2 (0.8 g, 2.5 mmol) in
CH2Cl2 (200 mL) was added dropwise trimethylsilyl cyanide
(7.3 g, 74 mmol), and the mixture was stirred under an argon
atmosphere at 40 °C for 20 h. The reaction mixture was
washed with water and brine and filtered through Celite. The
filtrate was concentrated. The residue was suspended in
toluene (200 mL), and trifluoroacetic acid (14 mL, 0.18 mol)
was added. The mixture was stirred under refluxing for 1.5 h
and then cooled. The reaction mixture was poured into water
and extracted with EtOAc. The extract was washed with brine,
dried, and concentrated. The residue was purified by column
chromatography (hexane:EtOAc 9:1) to afford 4.5 g (42% yield)
1
of 11 as an oily product. H NMR (CDCl3): δ 3.57 (d, 2H, J )
2.2 Hz), 3.87 (s, 3H), 6.90 (dd, 1H, J ) 2.2 Hz, 8.2 Hz), 7.11
(d, 1H, J ) 2.2 Hz), 7.32-7.35 (m, 1H), 7.39 (d, 1H, J ) 8.2
Hz).
Meth od O. N-[2-(6-Eth oxy-2,3-d ih yd r o-1H-in d en -1-yl)-
eth yl]p r op ion a m id e (21a ). To a suspension of 20 (1.0 g, 4.3
mmol) and potassium carbonate (3.0 g, 21 mmol) in N,N-
dimethylformamide (10 mL) was added dropwise iodoethane
(6.7 g, 43 mmol), and the mixture was stirred under reflux for
1.5 h. After it was cooled, the reaction mixture was poured
into water and extracted with EtOAc. The extract was
concentrated, and the residue was purified by column chro-
matography (EtOAc:hexane 85:15) and recrystallized from
EtOAc-hexane to afford 0.86 g (77% yield) of 21a ; mp 87-89
Meth od J . 2,3-Dih yd r o-6-m eth oxy-1H-in d en e-1-a cetic
Acid Eth yl Ester (14). To a suspension of 60% NaH (1.8 g,
46 mmol; dispersion in oil) in THF (200 mL) was added triethyl
phosphonoacetate (10 g, 46 mmol) in an ice-water bath, and
the mixture was stirred until it became homogeneous. To the
mixture was added a suspension of 3c (7.1 g, 44 mmol) in THF
(30 mL), and the stirring was continued at room temperature
for 2 h and then at 70 °C for 12 h. The reaction mixture was
diluted with water and extracted with EtOAc. The extract was
washed with water and brine, dried, and concentrated. The
residue was diluted with EtOH (200 mL), and 5% Pd-C (2.5
g, water 50%) was added. The mixture was stirred under a
hydrogen atmosphere (normal pressure) at 50 °C for 1.5 h. It
was then filtered, and the filtrate was concentrated. The
residue was purified by column chromatography (hexane:
EtOAc 97:3, followed by 4:1) to afford 6.6 g (64% yield) of 14
as an oily product. 1H NMR (CDCl3): δ 1.28 (t, 3H, J ) 7.2
Hz), 1.67-1.83 (m, 1H), 2.30-2.47 (m, 2H), 2.69-2.95 (m, 3H),
3.47-3.62 (m, 1H), 3.78 (s, 3H), 4.18 (q, 2H, J ) 7.2 Hz), 6.69-
6.75 (m, 2H), 7.11 (d, 1H, J ) 8.6 Hz).
Meth od K. 2,3-Dih yd r o-6-m eth oxy-1H-in d en e-1-eth a -
n ol (15). To a stirring suspension of lithium aluminum hydride
(1.1 g, 28 mmol) in THF (150 mL) was added dropwise a
solution of 14 (6.5 g, 28 mmol) in THF (20 mL) in an ice-water
bath, and the stirring was continued for 15 min. To the
reaction mixture was added water (1.0 mL), EtOAc, MgSO4,
and Celite, and then, the mixture was filtered. The filtrate
was concentrated to afford 5.0 g (93% yield) of 15 as an oily
product. 1H NMR (CDCl3): δ 1.35 (br s, 1H), 1.60-1.82 (m,
2H), 2.06-2.41 (m, 2H), 2.69-2.96 (m, 2H), 3.15-3.28 (m, 1H),
3.75-3.88 (m, 2H), 3.79 (s, 3H), 6.68-6.79 (m, 2H), 7.12 (d,
1H, J ) 8.0 Hz).
1
°C. H NMR (CDCl3): δ 1.00 (t, 3H, J ) 7.7 Hz), 1.31 (t, 3H,
J ) 7.0 Hz), 1.39-1.71 (m, 2H), 1.80-2.00 (m, 1H), 2.07 (q,
2H, J ) 7.7 Hz), 2.15-2.33 (m, 1H), 2.59-2.89 (m, 2H), 2.91-
3.08 (m, 1H), 3.14 (q, 2H, J ) 7.7 Hz), 3.97 (q, 2H, J ) 7.0
Hz), 6.66 (d, 1H, J ) 2.4 Hz), 6.75 (d, 1H, J ) 2.4 Hz), 7.07 (d,
1H, J ) 8.1 Hz), 7.79 (br s, 1H). Anal. (C16H23NO2) C, H, N. A
similar procedure was used to prepare the following com-
pounds: N-[2-(2,3-dihydro-6-propoxy-1H-inden-1-yl)ethyl]pro-
pionamide (21b) and N-[2-[2,3-dihydro-6-(1-methylethoxy)-1H-
inden-1-yl]ethyl]propionamide (21c).
Meth od P . (S)-N-[2-(2,3-Dih yd r o-6-m eth oxy-1H-in d en -
1-yl)eth yl]a ceta m id e ((S)-8c) a n d (R)-N-[2-(2,3-Dih yd r o-
6-m eth oxy-1H-in d en -1-yl)eth yl]a ceta m id e ((R)-8c). The
racemate 8c was resoluted with HPLC to afford optically pure
(S)-8c and (R)-8c [column, Ceramospher RU-1 (6.0 mm × 250
mm), 50 °C; eluent, MeOH; flow rate, 0.6 mL/min; detect, 290
nm; tR of (S)-8c, 50.3 min; tR of (R)-8c, 45.9 min]. Compound
20
20
(S)-8c: [R]D -1.5° (c 0.35, CHCl3); [R]Hg365 +80.7° (c 0.35,
CHCl3); mp 93-94 °C (EtOAc/hexane). Anal. (C14H19NO2) C,
H, N. Compound (R)-8c: [R]D20 +1.2° (c 0.30, CHCl3); [R]Hg365
20
-61.3° (c 0.30, CHCl3); mp 95-96 °C (EtOAc/hexane). Anal.
1
(C14H19NO2) C, H, N. H NMR data of the chiral compounds
were identical with those of 8c.
Met h od Q. (R)-2,3-Dih yd r o-6-m et h oxy-1H -in d en e-1-
eth a n a m in e Hyd r och lor id e ((R)-5c). Under an argon at-
mosphere, a mixture of (R)-8c (1.0 g, 4.3 mmol) and hydrazine
monohydrate (20 mL) was stirred under reflux for 24 h. To
the reaction mixture was added brine, and the mixture was
extracted with CHCl3. The extract was washed with brine,
dried, and concentrated. The residue was diluted with EtOH
(1 mL), and 4 M HCl/EtOH (1.5 mL) was added. To the solution
was added diethyl ether, and the solid that precipitated was
collected by filtration. The crude solid was recrystallized from
EtOH-diethyl ether to afford 0.78 g (80% yield) of (R)-5c;
Meth od L. 1-(2-Br om oeth yl)-2,3-d ih yd r o-6-m eth oxy-
1H-in d en e (16). To a stirring solution of 15 (5.0 g, 26 mmol)
in CH2Cl2 (100 mL) was added phosphorus tribromide (0.86
mL, 27 mmol) at -5 °C, and the stirring was continued for 30
min. The reaction mixture was diluted with water and
extracted with CHCl3. The extract was washed with water and
brine, dried, and concentrated. The residue was purified by
column chromatography (hexane:EtOAc 7:3, followed by 1:1)
1
to afford 1.8 g (27% yield) of 16 as an oily product. H NMR
20
1
(CDCl3): δ 1.60-1.78 (m, 1H), 1.88-2.06 (m, 1H), 2.24-2.41
(m, 2H), 2.70-2.96 (m, 2H), 3.21-3.38 (m, 1H), 3.41-3.60 (m,
2H), 3.79 (s, 3H), 6.68-6.78 (m, 2H), 7.12 (d, 1H, J ) 7.6 Hz).
Meth od M. 2,3-Dih yd r o-6-m eth oxy-1H-in d en e-1-p r o-
p a n en itr ile (17). To a solution of 16 (1.8 g, 6.9 mmol) in
dimethyl sulfoxide (80 mL) was added sodium cyanide (0.35
g, 7.2 mmol), and the mixture was stirred at 60 °C for 40 min.
The reaction mixture was diluted with water and extracted
[R]D +32.6° (c 0.18, H2O); mp 183-185 °C. H NMR data of
(R)-5c were identical with those of 5c hydrochloride. The
enantiomeric excess of (R)-5c was determined by HPLC as
>99% [column, CHIRAL-AGP (4.0 mm × 100 mm), room
temperature; eluent, 10 mM phosphate buffer (pH 7.0)-
acetonitrile (9:1); flow rate, 0.5 mL/min; detect, 280 nm; tR of
(R)-5c, 19.2 min; tR of (S)-5c (enantiomer of (R)-5c), 23.6 min].
A similar procedure was used to prepare compound (S)-5c.

4220 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19
Fukatsu et al.
Meth od R. Asym m etr ic Hyd r ogen a tion . (S)-8d . A mix-
ture of (E)-9a (3.5 g, 14 mmol) and Ru(OCOCH3)2[(S)-binap]
(0.12 g, 14 mmol) in degasified absolute methanol (70 mL) was
stirred at 70 °C for 3 h in an autoclave (hydrogen pressure,
9.1 MPa). The reaction mixture was concentrated, and the
residue was purified by column chromatography (hexane:
EtOAc 1:9) and recrystallized from EtOAc-hexane to yield 2.9
material is available free of charge via the Internet at http://
pubs.acs.org.
Note Ad d ed a fter ASAP P ostin g. This manuscript
was released ASAP on 8/15/2002 with an error in the
leftmost structure in Table 2. The correct version was
posted on 9/5/2002.
20
g (83%) of (S)-8d : [R]D -7.0° (c 1.00, EtOH); mp 76-77 °C.
1H NMR (CDCl3): δ 1.15 (t, 3H, J ) 7.8 Hz), 1.50-1.80 (m,
2H), 1.98-2.40 (m, 2H), 2.20 (q, 2H, J ) 7.6 Hz), 2.68-2.97
(m, 2H), 3.04-3.20 (m, 1H), 3.39 (dd, 2H, J ) 7.2 Hz, 13.2
Hz), 3.79 (s, 3H), 5.45 (br s, 1H), 6.68-6.76 (m, 2H), 7.12 (d,
1H, J ) 8.0 Hz). Anal. (C15H21NO2) C, H, N. The enantiomeric
excess of (S)-8d was determined by HPLC as >99% [column,
CHIRALPAK AS (4.6 mm × 250 mm), room temperature;
eluent, hexane-2-propanol-trifluoroacetic acid (90:10:0.1); flow
rate, 1.0 mL/min; detect, 290 nm; tR of (S)-8d , 28.0 min; tR of
(R)-8d (enantiomer of (S)-8d ), 23.6 min].
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and Prusoff.21
Ack n ow led gm en t. We thank Mr. Akira Fujishima
and Ms. Keiko Higashikawa for X-ray crystallographic
analysis. Thanks also to Mr. Nobuhiro Fujii and Mr.
Masaki Setoh for technical assistance.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data of (S)-8o; detailed information on the synthesis
and characterization of the target compounds listed in Table
2; a list of receptors and enzymes tested for (S)-8d ; the
inhibitory effect of (S)-8d on forskolin-induced cAMP produc-
tion in CHO cells expressing the human MT1 receptor. This

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