Synthesis of naphthalenic melatonin receptor ligands

Article abstract of DOI:10.1081/SCC-100000591

A highly efficient and versatile synthetic approach to the synthesis of naphthalenic analogs of melatonin, compound 7, and its 2-alkyl substituted analog 8 is described. This approach features the novel synthesis of substituted 1-naphthyl acetonitrile 12 and 19 by nucleophilic addition of LiCH₂CN to substituted 1-tetralone, followed by aromatization via a 2-step reaction sequence, dehydrogenation with DDQ and TsOH catalyzed dehydration.

Full text of DOI:10.1081/SCC-100000591

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SYNTHESIS OF NAPHTHALENIC MELATONIN RECEPTOR
LIGANDS
Guo-Hua Chu a & Pui-Kai Li b
a College of Pharmacy, The Ohio State University, Columbus, Ohio, 43210, U.S.A.
b College of Pharmacy, The Ohio State University, Columbus, Ohio, 43210, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Guo-Hua Chu & Pui-Kai Li (2001) SYNTHESIS OF NAPHTHALENIC MELATONIN RECEPTOR LIGANDS,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:4,
621-629, DOI: 10.1081/SCC-100000591
To link to this article: http://dx.doi.org/10.1081/SCC-100000591
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SYNTHETIC COMMUNICATIONS, 31(4), 621–629 (2001)
SYNTHESIS OF NAPHTHALENIC
MELATONIN RECEPTOR LIGANDS
Guo-Hua Chu and Pui-Kai Li∗
College of Pharmacy, The Ohio State University,
Columbus, Ohio 43210
ABSTRACT
A highly efficient and versatile synthetic approach to the syn-
thesis of naphthalenic analogs of melatonin, compound 7, and its
2-alkyl substituted analog 8 is described. This approach features
the novel synthesis of substituted 1-naphthyl acetonitrile 12 and
19 by nucleophilic addition of LiCH2CN to substituted 1-tetralone,
followed by aromatization via a 2-step reaction sequence, dehydro-
genation with DDQ and TsOH catalyzed dehydration.
The pineal hormone melatonin 1 is involved in circadian rhythms, retinal
physiology, seasonal breeding, and cardiovascular regulation (1–3). Melatonin also
appears to be involved in a number of pathological conditions, and there is strong
evidence for its use in pathologies associated with disorders in circadian rhythm.
The administration of melatonin in humans was shown to alleviate jet lag (4), to
induce sleep (5), and to advance the sleep rhythm of subjects with delayed sleep
phase syndrome (6). Melatonin may mediate its effect in vivo through melatonin
receptors. Presently, two human melatonin receptor subtypes exist and are now de-
fined as either the mt1 (7) (formerly known as the Mel1a receptor) (8) and the MT2
∗Corresponding author.
621
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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622
CHU AND LI
(7) (formerly known as the Mel1b receptor) (9). The therapeutic use of melatonin is
limited by its short biological half-life (10), despite its involvement in many possi-
ble physiological processes. Thus, synthetic analogs of melatonin were designed.
It has been known that the indole ring of melatonin is not crucial for melatonin
receptor recognition. For instance, the naphthalene ring (11–20) can serve as a
bioisostere of the indole nucleus of melatonin, and analog 2 was reported to have
equivalent affinity to melatonin for melatonin receptors in ovine pars tuberalis (11)
and is currently in clinical trial. In addition to naphthalene, other groups such as
amidotetralin (21), methoxychroman (22), amido indane (23), benzofuran (18,24),
benzothiophene (18,24), and quinoline (25) can serve as a bioisostere of the indole
nucleus of melatonin. Langlois et al. reported that the addition of a 2-methoxy
group (OMe) to compound 2 to form 3 results in an order of magnitude increase in
receptor affinity over compound 2 (Fig. 1) (12). It was postulated that the 2-OMe
group binds to the accessory binding site of the receptor. Other 2-substituted naph-
thalenic melatonin receptor ligands were also reported (16). Two of the ligands are
N-[2-(2-trimethylammoniumethyleneoxy-7-methoxy-1-naphthyl)ethyl]propion-
amide iodide 4 (TMEPI) (16) and N-[2-(2-bromo-acetoxy-7-methoxy-1-naphthyl)
ethyl] propionamide 5 (BMNEP) (17). TMEPI is the first melatonin receptor ana-
log that contains a permanently charged moiety and is a potential agent to study
melatonin receptor regulation. BMNEP is the first irreversible melatonin receptor
ligand that is reported to selectively alkylate MT2 melatonin receptor. Recently,
the synthesis of 3-alkyl substituted analog of 2 containing a fluorescent probe
(compound 6), a potential agent to be used to localize the cellular distribution of
melatonin receptor, was reported (20). However, the strategy to synthesize 2-alkyl
substituted naphthalenic melatonin analog has never been reported.
O
O
N
N
H
H
CH3O
CH3O
N
H
Melatonin 1
2
O
O
N
H
OR′
N
H
CH3O
CH3O
H
(CH2)2N
NO2
+I−
3
4
5
R = CH3
6
N
N
CH3
CH3
CH3
O
R = CH2CH2N
R = COCH2Br
Figure 1.

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NAPHTHALENIC MELATONIN RECEPTOR LIGANDS
623
Due to the importance of the naphthalenic bioisostere 2 and its 2-substituted
analogs, we report a new efficient synthetic scheme for naphthalene analog 7
(a homolog of 2) and its 2 alkyl substituted analog 8 (N-[2-(2-Benzyl 7-methoxy-
1-naphthyl)ethyl] propionamide).
O
O
N
N
H
H
CH3O
CH3O
CH2Ph
7
8
For the synthesis of naphthalenic melatonin analog 7, the commercially
available 7-methoxy-1-tetralone (9) was used as the starting material (Scheme 1).
Reaction of 9 with LiCH2CN, which was prepared by treatment of acetonitrile with
n-butyl lithium, gave the tertiary alcohol 10 (95%). Treatment of compound 9 with
DDQ afforded the dehydrogenated product 11 (90.7%), which was unstable and
immediately subjected to acid-catalyzed dehydrogenation, yielding the key inter-
mediate: nitrile 12 (88.2%). Reduction of nitrile 12 with LiAlH4 gave the amine 13,
which was acylated with propionyl chloride, furnishing target compound 7 (54%
from 12). Although there is a known procedure for the synthesis of the key inter-
mediate, nitrile 12 (26), compared to the literature method, our method reported
here is much more efficient and versatile. The versatility of this new method was
further illustrated by its application to the synthesis of 2-alkyl substituted analog 8.
7-Methoxy-1-tetralone 9 was also used as the starting material for the syn-
thesis of analog 8 (Scheme 2). Treatment of 9 with LiHMDS, followed by excess
O
HO
CH2CN
HO
CH2CN
CH3O
CH3O
CH3O
a
b
9
10
11
c
O
CH2CH2NHCC2H5
e
CH2CH2NH2
d
CH2CN
CH3O
CH3O
CH3O
7
13
12
Reagents and Conditions: a. LiCH2CN, THF, −78◦C, lh, 95%; b. DDQ, CH2Cl2, rt,
overnight, 90.7%; c. TsOH, benzene, reflux, 1h, 88.2%; d. LiAlH4, THF, 45–50◦C,
overnight; e. C2H5COCl, Et3N, CH2Cl2, 0◦C to r.t, 1h, 54% from 12.
Scheme 1.

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CHU AND LI
O
O
O
Ph
CH3O
CH2Ph
CH2Ph
CH3O
CH3O
a
b
14
9
15
c
O
HO
CH2CN
CH2Ph
HO
CH2CN
CH2Ph
CH3O
CH3O
CH3O
CH2Ph
e
d
18
17
16
f
O
CH2CN
CH2Ph
CH2CH2NHCC2H5
CH2Ph
CH3O
CH3O
g, h
19
8
Reagents and Conditions: a. i. LiHMDS, THF, −78◦C, 30 min; ii. PhCH2Br, −78◦C to r.t,
overnight; b. PhCHO, NaOH, THF-EtOH-H2O, r.t, 6 days, 88%; c. H2, 10% Pd/C, r.t, 2h,
80%; d. LiCH2CN, −78◦C, 1h, 87%; e. DDQ, CH2Cl2, r.t, overnight; f. TsOH, PhH, reflux,
1h, 50.4% from 17; g. LiAlH4, THF, 50◦C, overnight; h. C2H5COCl, Et3N, CH2Cl2, 0◦C to
r.t, 1h, 31.3%.
Scheme 2.
benzyl bromide, gave the dibenzylated product 14 as the major product. Then a
two-step reaction sequence was used to prepare the monobenzylated compound 16.
Condensation of 8 with benzaldehyde yielded α,β-unsaturated ketone 15 (88%),
which was then hydrogenated to afford the desired compound 16 (80%). Reac-
tion of ketone 16 with the anion generated from acetonitrile by treatment with
LiHMDS yielded the nitrile 17 (87%). The configurations 5 of the hydroxy and
benzyl group at C-1 and C-2 position were not elucidated; however, the nucle-
ophilic attack at the C-1 position of compound 16 by the acetonitrile would favor
the opposite side of the benzyl group at the C-2 position. Furthermore, it was
unnecessary to determine the configuration at C-1 and C-2 position of compound
17 because it would be aromatized and the two stereo centers would be elim-
inated. Compound 17 was then treated with DDQ followed by acid-catalyzed
dehydration, yielding the aromatized product 19 (50.4% for 2 steps). Finally,
nitrile 19 was reduced with LiAlH4 and the resulting amine was acylated by
treatment with propionyl chloride, leading to the target compound 8 (31.3% for
2 steps).

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NAPHTHALENIC MELATONIN RECEPTOR LIGANDS
EXPERIMENTAL
625
Chemicals and silica gel were purchased from Aldrich Chemical Company
(Milwaukee, WI). The chemicals were checked for purity by thin layer chromatog-
raphy and NMR. Melting points were determined on a Thomas Hoover capillary
melting point apparatus and are uncorrected. Proton NMR spectra were obtained
with a Bruker WH-300 (300 MHz) spectrophotometer. Elemental analyses were
performed by Atlantic Microlab Inc. (Norcross, GA).
1-Hydroxy-7-methoxy-1,2,3,4-tetrahydro-1-naphthyl
Acetonitrile (10)
To a solution of acetonitrile (1.47 mL, 28 mmol) in anhydrous THF (50 mL)
at 78◦C was added dropwise 17.5 mL of n-BuLi (1.6 M in hexane, 28 mmol)
under nitrogen. The mixture was then added a solution of 7-methoxy-1-tetralone
9 (3.52 g, 20 mmol) in THF (25 mL). After the addition, the solution was stirred at
−78◦C for 1 h and quenched with saturated aqueous solution of NH4Cl(80 mL),
extracted with EtOAc (3 × 80 mL). The organic extracts were dried (Na2SO4)
and concentrated under reduced pressure. The residue was purified by silical
gel chromatography using petroleum ether: CH2Cl2: EtOAc (3:1:1) as eluent,
1
yielding pure product 10 (4.13 g, 95%). m.p: 90.5◦–91◦C; HNMR (300 MHz,
CDCl3) δ 1.78–2.25 (m, 4H), 2.40 (s, 1H, OH), 2.70 (m, 2H), 2.75, 2.87
(2d, 2H, J = 16.8 Hz), 3.77 (s, 3H, OCH3), 6.77 (dd, 1H, J = 2.7, 8.4 Hz, ArH),
7.0 (d, 1H, J = 8.4 Hz, ArH), 7.07 (d, 1H, J = 2.7 Hz, ArH). Analysis calcu-
lated for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.62; H, 6.99; N,
6.57.
1-Hydroxy-7-methoxy-3,4-dihydro-1-naphthyl Acetonitrile (11)
To a solution of compound 10 (434 mg, 2 mmol) in CH2Cl2 (16 mL) was
added DDQ (545 mg, 2.4 mmol). The reaction mixture was stirred at r.t overnight,
then diluted with a mixture of petroleum ether : CH2Cl2 (2:1, 20 ml) and filtered.
The filtrate was concentrated and the residue was purified by silica gel chromatog-
raphy using petroleum ether : CH2Cl2 : EtOAc (3:1:1) as eluent, affording olefin
11 (390 mg, 90.7%) as an oil. 1H NMR (300 MHz, CDCl3) δ 2.45–2.77 (m, 5H),
3.79 (s, 3H, OCH3), 5.83 [m, 1H, (HC = CH-CH2)], 6.42 (dd, 1H, J = 2.7, 9.6 Hz,
Ar-CH = ), 6.77 (dd, 1H, J = 2.7, 8.4 Hz, ArH), 7.0 Hz (d, 1H, J = 8.4 Hz, ArH),
7.19 (d, 1H, J = 2.7 Hz, ArH). Olefin 11 was unstable and immediately used for
the next step.

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CHU AND LI
7-Methoxy-1-naphthyl Acetonitrile (12)
To a solution of compound 11 (2.4 g, 11.2 mmol) in benzene (100 mL) was
added TsOH.H2O (103 mg, 0.54 mmol). The reaction mixture was refluxed for
1 h, cooled down to r.t, and washed with saturated aqueous solution of NaHCO3
(2 × 40 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo.
The residue was purified by silica gel chromatography using petroleum ether :
CH2Cl2: EtOAc (3:1:1) as eluent, furnishing pure nitrile 12 (1.94 g, 88.2%). m.p:
1
83.5◦–84.5◦C (lit. (27): 83◦–85◦C); H NMR (300 MHz, CDCl3) δ 3.94 (s, 3H,
OCH3), 4.04 (s, 2H, ArCH2), 7.04 (d, 1H, J = 2.1 Hz, ArH), 7.19–7.78 (m, 5H,
ArH).
N-[2-(7-methoxy-1-naphthyl)ethyl]propionamide (7)
To a suspension of LiAlH4 (1.3 g, 34.2 mmol) in anhydrous THF at 0◦C was
added dropwise a solution of nitrile 12 (2 g, 10.2 mmol). The reaction mixture
was stirred at r.t for 30 min, then at 45◦–50◦C overnight. The reaction mixture
was cooled with ice bath and quenched carefully by dropwise addition of water
(4.0 mL). The resulting mixture was stirred at r.t for 30 min and filtered through
a pad of celite. The filtrate was concentrated in vacuo, giving the crude amine 13,
which was used directly for the next step.
The crude amine 13 was dissolved in anhydrous CH2Cl2 (60 mL) and cooled
withicebath. Tothissolutionwasaddedtriethylamine(3mL, 21.6mmol), followed
by dropwise addition of propionyl chloride (1.4 mL, 16.1 mmol). The reaction
mixture was allowed to warm to r.t and washed with saturated aqueous solution
of NaHCO3 (2 × 30 ml), dried (Na2SO4) and concentrated in vacuo. The residue
was purified by silica gel chromatography using petroleum ether: CH2Cl2 : EtOAc
(1:1:1) as eluent, yielding the pure amide 7 (1.41 g, 54% for 2 steps) m.p: 103◦ −
104◦C (lit. (11): 103◦C). 1HNMR (300 MHz, CDCl3) δ 1.09 (t, 3H, J = 7.5 Hz,
CH3), 2.12 (q, 2H, J = 7.5 Hz, CH2CO), 3.21 (t, 2H, J = 7.2 Hz, ArCH2), 3.59
(m, 2H, CH2N), 3.94 (s, 3H, OCH3), 5.60 (br s, 1H, NH), 7.13 (dd, 1H, J = 2.4,
9.0 Hz, ArH), 7.20–7.65 (m, 4H, ArH), 7.72 (d, 1H, J = 9.0 Hz, ArH).
2-Phenylmethylene-7-methoxy-1-tetralone (15)
To the solution of tetralone 9 (2.12 g, 12 mmol) in a mixture of EtOH :
THF (25 mL : 6 mL) was added a solution of NaOH (3.6 g, 90 mmol) in water
(70 mL) and followed by the addition of benzaldehyde (1.28 g, 12.1 mmol). The
reaction mixture was stirred at r.t for 6 days and diluted with water (160 mL).
The crude product was obtained by filtration as a yellow solid, which was purified

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NAPHTHALENIC MELATONIN RECEPTOR LIGANDS
627
by silica gel chromatography using petroleum ether: CH2Cl2 : EtOAc (3:1:1) as
eluent, yielding pure condensed product 15 (2.8 g, 88%). m.p: 115.5◦ −116.5◦C.
1HNMR (300 MHz, CDCl3) δ 2.86 (t, 2H, J = 6.0 Hz, CH2), 3.09 (t, 2H, J = 6.0
Hz, CH2), 3.85 (s, 3H, OCH3), 7.05 (dd, 1H, J = 2.7, 8.4 Hz, ArH), 7.15 (d, 1H,
J = 8.4 Hz, ArH), 7.32–7.42 (m, 5H, ArH), 7.61 (d, 1H, J = 2.7 Hz, ArH), 7.85 (s,
1H, CH =). Analysis calculated for C18H16O2: C, 81.79; H, 6.10. Found: C, 81.96;
H, 5.98.
2-Benzyl-7-methoxy-1-tetralone (16)
α, β-Unsaturated ketone 15 (3.9 g, 14.77 mmol) in EtOAc (200 mL) was
hydrogenated at r.t in the presence of 10% Pd/C for 2 h. The reaction mixture
was filtered and the filtrate was concentrated in vacuo. The residue was purified
by silica gel chromatography using petroleum ether : EtOAc : CH2Cl2 (3:1:1) as
1
eluent, giving pure compound 16 (3.15 g, 80%) m.p: 116◦ −117.5◦C. HNMR
(300 MHz, CDCl3) δ 1.77 (m, 1H), 2.09 (m, 1H), 2.60–2.89(m, 4H), 3.48 (dd, 1H,
J = 3.0, 13.0 Hz), 3.84 (s, 3H, OCH3), 7.04 (dd, 1H, J = 2.7, 8.4 Hz, ArH), 7.13
(d, 1H, J = 8.4 Hz, ArH), 7.19–7.33 (m, 5H, ArH), 7.55 (d, 1H, J = 2.7 Hz, ArH).
Analysis calculated for C18H18O2: C, 81.17; H, 6.81. Found: C, 81.02; H, 6.98.
1-Hydroxy-2-benzyl-7-methoxy-1,2,3,4-tetrahydro-1-naphthyl
Acetonitrile (17)
The synthesis of acetonitrile 17 is similar to the procedure for the synthesis
of 10. From 2 g (7.52 mmol) of 16, two grams (87%) of nitrile 17 were obtained
after purification by silica gel chromatography. m.p: 187◦ −188◦C; 1H NMR (300
MHz, DMSO-d6) δ 1.61 (m, 2H), 2.04–2.74 (m, 4H), 2.92 (s, 2H), 3.25 (m, 1H),
3.79 (s, 3H, OCH3), 5.69 (s, 1H, OH), 6.79 (dd, 1H, J = 2.1, 8.4 Hz, ArH), 6.97
Hz (d, 1H, J = 8.4 Hz, ArH), 7.19–7.31 (m, 6H, ArH). Analysis calculated for
C20H21NO2: C, 78.15; H, 6.89; N, 4.56. Found: C, 78.41; H, 6.76; N, 4.37.
2-Benzyl-7-methoxy-1-naphthyl Acetonitrile (19)
The synthesis of 19 is similar to the procedure for the synthesis of 12. From
1.4 g (7.52 mmol) of 17, 660 mg (50.4%) of compound 19 was obtained after
purification by silica gel chromatography. m.p: 105◦–106◦C; 1H NMR (300 MHz,
CDCl3) δ 3.95 (s, 3H, OCH3), 4.24 (s, 2H, CH2CN), 7.09–7.29 (m, 7H, ArH),
7.75 (m, 2H, ArH). Analysis calculated for C20H17NO: C, 83.60; H, 5.96; N, 4.87.
Found: C, 83.78; H, 5.67; N, 4.55.

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N-[2-(2-Benzyl-7-methoxy-1-naphthyl)ethyl]propionamide (8)
The synthesis of 8 is similar to the procedure for the synthesis of 7. From
0.66 g (7.52 mmol) of 19, 250 mg (31.3%) of compound 8 was obtained after
1
purification by silica gel chromatography. m.p: 117.5◦ −118.5◦C; HNMR (300
MHz, CDCl3) δ 1.07 (t, 3H, J = 7.5 Hz, CH3), 2.08 (q, 2H, J = 7.5 Hz, CH2CO),
3.25 (m, 4H, ArCH2 and CH2CN), 3.97 (s, 3H, OCH3), 4.18 (s, 2H, ArCH2Ph),
5.45 (br s, 1H, NH), 7.10–7.22 (m, 7H, ArH), 7.57 (d, 1H, J = 2.7 Hz, ArH), 7.59
(d, 1H, J = 8.7 Hz, ArH), 7.68 (d, 1H, J = 8.7 Hz, ArH). Analysis calculated for
C23H25NO2: C, 79.51; H, 7.25; N, 4.03 Found: C, 79.52; H, 7.31; N, 4.09.
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Accepted March 29, 2000

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