Alternative and straightforward synthesis of dopaminergic 5-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine

Article abstract of DOI:10.1080/00397911.2010.495043

5-Methoxy-1,2,3,4-tetrahydronaphthalen-2-amine was synthesized from 2-naphthoic acid in six steps with an overall yield of 27%. Following the reaction sequence, bromination, esterification, substitution with NaOMe in the presence of CuI, the Birch reducti

Full text of DOI:10.1080/00397911.2010.495043

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Alternative and Straightforward
Synthesis of Dopaminergic
5-Methoxy-1,2,3,4-
tetrahydronaphthalen-2-amine
Necla Öztaşkın a , Süleyman Göksu a & Hasan Seçen a
a Department of Chemistry, Faculty of Science, Ataturk University,
Erzurum, Turkey
Version of record first published: 02 May 2011.
To cite this article: Necla Öztaşkın , Süleyman Göksu & Hasan Seçen (2011): Alternative and
Straightforward Synthesis of Dopaminergic 5-Methoxy-1,2,3,4-tetrahydronaphthalen-2-amine,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:13, 2017-2024
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Synthetic Communications1, 41: 2017–2024, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.495043
ALTERNATIVE AND STRAIGHTFORWARD SYNTHESIS
OF DOPAMINERGIC 5-METHOXY-1,2,3,4-
TETRAHYDRONAPHTHALEN-2-AMINE
¨
¨
Necla Oztas¸kın, Su¨leyman Goksu, and Hasan Sec¸en
Department of Chemistry, Faculty of Science, Ataturk University,
Erzurum, Turkey
GRAPHICAL ABSTRACT
Abstract 5-Methoxy-1,2,3,4-tetrahydronaphthalen-2-amine was synthesized from
2-naphthoic acid in six steps with an overall yield of 27%. Following the reaction sequence,
bromination, esterification, substitution with NaOMe in the presence of CuI, the Birch
reduction, Curtius rearrangement, and hydrogenolysis afforded biologically active title
compound 5-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine as hydrogen chloride salt.
Keywords Aminotetralin; Birch reduction; Curtius rearrangement; dopamine;
neurotransmitter; synthesis
Dopamine (1), a hormone-like neurotransmitter compound, plays an important role
in central nervous system (CNS)–related disorders such as schizophrenia and Parkin-
son’s disease.[1] Many chemical compounds have dopamine-like actions.[2]
2-Amino-1,2,3,4-tetrahydronaphthalene-6,7-diol (6,7-ADTN; 2)[3] and 2-amino-
1,2,3,4-tetrahydronaphthalene-5,6-diol (5,6-ADTN; 3),[4] dopamine-like com-
pounds, are potential agonists at dopamine receptors. Apomorphine (APM 4), a
potent dopamine agonist drug, has been tried for a variety of uses including psychi-
atric treatment and the treatment of neurological disorders, Parkinson’s disease, and
erectile dysfunction.[5]
McDermed and coworkers have reported that hydrogen iodide salt of levo
enantiomer of aminotetralin 5 has the same dopaminergic activity as that of
APM.[6] Hacksell et al. investigated the central dopamine-receptor stimulating
activity of 6, 7, and some N-ethyl, methyl, and propyl derivatives of these com-
pounds. They experimentally demonstrated that especially N-alkylated derivatives
have important stimulating activities.[7] Binding assays of compounds 5–7 and their
Received May 1, 2010.
Address correspondence to Suleyman Go¨ksu, Department of Chemistry, Faculty of Science,
¨
Ataturk University, 25240 Erzurum, Turkey. E-mail: sgoksu@atauni.edu.tr
2017

¨ ¨
N. OZTAS¸KIN, S. GOKSU, AND H. SEC¸ EN
2018
N-arylalkyl substituents for human dopamine D2, D3, and D4 receptors have been
evaluated by van Vliet et al. According to their experimental results, (S)-5-
OH-DPAT 5 is more active at D2 and D3 receptors than 7.[8] N,N-Dipropyl substitu-
ent of (R)-6 has important agonist activity at the dopamine D2A receptor.[9]
a-Adrenergic activity of 6 has been investigated by DeMarinis et al.[10] Compound
6 and its N-alkyl substituents are potent monoamine oxidase inhibitors. N-
Methylated substituent of this compound is an analgesic.[11] The title compound,
5-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine (6), and some of its N-alkylated
derivatives have been studied for 5-hydroxytryptaminergic (5-HT) actions in 5-HT
receptors[12a,12b] and for their binding affinities at a1-, a2-, b-adrenergic; muscarinic;
dopamine D1, D2, and D3; and serotonin 5HT1A and 5-HT2 receptors.[12c] Com-
pounds 6, 7, and their N-alkylated compounds are also important antifungal
agents.[13] Aminotetralin 7 has been defined as a tyramine analog and acts as an
inhibitor of phenylethanolamine N-methyltransferase.[14]
To the best of our knowledge, the known procedures for the synthesis of 6 and
its N-alkyl derivatives are based on the preparation of 1-tetralone or 2-tetralone,
which involves a number of steps. In the previous studies, the title compound has
been synthesized by a-amination or carboxylation of 1-tetralone and by reductive
amination of 2-tetralone.[7,8,10,13–15]
In our ongoing project on the synthesis of dopaminergic aminotetralines and
aminoindanes, we have already reported[16] concise syntheses of 6,7-ADTN (2),
5,6-ADTN (3), and 2-aminoindanes. In the present study, we describe an alternative
and straightforward synthesis of 5-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine
(6) as a hydrochloride salt starting with 2-naphthoic acid (8) in six steps.
Synthesis is started with 2-naphthoic acid (8). I2-catalyzed bromination of 8
with molecular bromine in AcOH at 118 ꢀC gave 5-bromo-2-naphthoic acid (9) with
a yield of 46%.[17] Esterification of 9 in MeOH in the presence of TsOH
(p-toluenesulfonic acid) gave the corresponding methyl ester 10 in good yield

5-METHOXY-1,2,3,4-TETRAHYDRONAPHTHALEN-2-AMINE
2019
(95%).[17] One of the critical steps of our synthesis was the substitution of bromine in
compound 10 with NaOMe. Copper-assisted nucleophilic substitutions of similar
aryl halides have been reported in our previous studies.[16c,18] By a similar approach,
the reaction of bromoester 10 with NaOMe in the presence of CuI followed by
NaOH-assisted hydrolysis of the residue in MeOH-H2O and subsequent acidification
of the residue afforded corresponding carboxylic acid 11.[19]
The second crucial step in the synthesis of 6 was the Birch reduction of
5-methoxy-2-naphthoic acid (11). Fortunately, the reaction of 11 with 4 mol. equiv.
of Na in liquid NH3 proceeded from the electron-deficient ring of 11, and acidifi-
cation of the residue provided 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-
carboxylic acid (12) in excellent yield (90%). In the next step, carboxylic acid 12
was converted to carbamate 13 by applying the procedure described in the literature
for the synthesis of 6,7-ADTN and 5,6-ADTN.[16a,16b,20] The Curtius reaction of 12
with diphenylphosphoryl azide in the presence of Et3N in benzene at 80 ꢀC for 6 h,
followed by treatment with benzyl alcohol at the same temperature for 30 h, afforded
13 with a yield of 90%. Hydrogenolysis of 13 in MeOH in the presence of CHCl3 (for
producing HCl) gave 14, a hydrochloride salt of 6, as a pure and sole product in
good yield (94%; Scheme 1).
In summary, we have achieved an alternative and convenient straightforward
synthesis of biologically important 5-methoxy-1,2,3,4-tetrahydronaphthalen-2-
amine (6) as a hydrochloride salt starting with 2-naphthoic acid (8) in six steps
with an overall yield of 27%. In addition, we synthesized 5-methoxy-1,2,3,4-
tetrahydronaphthalene-2-carboxylic acid (12), by an alternative method, and
Scheme 1. Synthesis of 2-aminotetralin 14. Reagents and conditions: (i) Br2 (I2, catalytic), AcOH, 118 ꢀC,
46%; (ii) MeOH=TsOH, 64 ꢀC, 95%; (iii) (1) NaOMe=MeOH, DMF, CuI, reflux; (2) NaOH=MeOH-H2O,
0–25 ꢀC then HCl, 80%; (iv) (1) Na, liq. NH3=THF; ꢁ70 ꢀC; (2) 37% aq. HCl; 90%; (v) (1) (PhO)2P(O)N3,
Et3N, C6H6, reflux; (2) PhCH2OH, reflux; 90%; and (vi) H2, Pd-C, MeOH=CHCl3, 25 ꢀC, 94%.

¨ ¨
N. OZTAS¸KIN, S. GOKSU, AND H. SEC¸ EN
2020
carbamate 13 for the first time, which can be important synthons for further biologi-
cal and synthetic purposes.
EXPERIMENTAL
All chemicals and solvents are commercially available and were used after dis-
tillation or treatment with drying agents. Melting points were determined on a capil-
lary melting apparatus (Buchi 530) and are uncorrected. Infrared (IR) spectra were
obtained from solutions in 0.1-mm cells with a Perkin-Elmer spectrophotometer.
1
The H and 13C NMR spectra were recorded on Varian spectrometers at 200 (50)
and 400 (100) MHz with Me4Si as the internal standard. Coupling constants are
reported in hertz (Hz). Multiplicity is defined as s (singlet), d (doublet), t (triplet),
br (broad), or m (multiplet). Elemental analyses were performed on a Leco
CHNS-932 apparatus. Electrospray ionization–mass spectra (ESI-MS) were per-
formed on a Bruker MicroTOF-Q. All column chromatography was performed on
silica gel (60 mesh, Merck). PLC is preparative thick-layer chromatography: 1 mm
of silica gel 60 PF (Merck) on glass plates.
5-Bromo-2-naphthoic Acid (9)
A solution of Br2 (10.00 g, 62.50 mmol) and I2 (0.3 g, catalytic) in AcOH
(10 mL) was added dropwise to a stirred solution of 2-naphthoic acid (8) (10.00 g,
58.12 mmol) in AcOH (40 mL) at 118 ꢀC over a period of 20 min. The reaction mix-
ture was stirred at the same temperature for 1 h. After the reaction mixture was
cooled down to 60 ꢀC (note: If the mixture is cooled to rt, further brominated pro-
ducts are also precipitated), solidified 9 was filtered and washed with hot H2O
(2 ꢂ 30 mL). Drying of the residue at 60 ꢀC and recrystallization from MeOH
afforded 5-bromo-2-naphthoic acid (9) (6.7 g, 46%). White crystals. Mp 266–
1
268 ꢀC (lit.[21] 267–269 ꢀC). H NMR (200 MHz, DMSO-d6): d 8.69 (bs, 1H, H-1),
8.23 (AB, d, J(3,4) ¼ 8.8 Hz, 1H, H-4), 8.21 (ABX, d, J(7,8) ¼ 7.7 Hz, 1H, H-8), 8.15
(AB, dd, J(3,4) ¼ 8.8 Hz, J(1,3) ¼ 1.6 Hz, 1H, H-3), 8.03 (ABX, d, J(6,7) ¼ 7.4 Hz, 1H,
H-6), 7.54 (ABX, quasi t, J ¼ 7.8 Hz, 1H, H-7), 3.40 (bs, OH). 13C NMR
(50 MHz, DMSO-d6): d 168.7, 135.4, 134.8, 134.0, 132.9, 131.5, 131.0, 129.3,
128.8, 128.6, 123.3.
Methyl 5-Bromo-2-naphthoate (10)
5-Bromo-2-naphthoic acid (9) (6.00 g, 24 mmol) was dissolved in MeOH
(60 mL). A catalytic amount of TsOH (90 mg) was added to this solution, and the
reaction mixture was refluxed for 24 h. After MeOH was evaporated, CHCl3
(80 mL) and H2O (60 mL) were added to this residue. The organic layer was sepa-
rated and washed with a saturated solution of Na2CO3 (3 ꢂ 10 mL). Drying of the
organic layer over Na2SO4, and evaporation of the solvent and crystallization from
AcOEt=hexane gave methyl 5-bromo-2-naphthoate (10) (6.00 g, 95%). White crys-
1
tals. Mp 70–72 ꢀC (lit.[17] 72–73 ꢀC). H NMR (200 MHz, DMSO-d6): d 8.56 (bs,
1H, H-1), 8.12–8.02 (m, 4H, H-3, H-4, H-6, and H-8), 7.46 (quasi t, J ¼ 7.8 Hz,
1H, H-2), 3.92 (s, methoxide, 3H). 13C NMR (50 MHz, DMSO-d6): d 167.5, 135.2,
134.8, 134.1, 132.8, 131.4, 129.6, 129.3, 128.6, 128.2, 123.3, 54.1.

5-METHOXY-1,2,3,4-TETRAHYDRONAPHTHALEN-2-AMINE
2021
5-Methoxy-2-naphthoic Acid (11)
Na (1.56 g, 67.83 mmol) was added to refluxed MeOH (90 mL) in small pieces
for 1 h under N2. To this solution was added a solution of 10 (6.00 g, 22.65 mmol) in
freshly distilled DMF (50 mL) over CaH2. While the reaction mixture was being
refluxed, CuI (100 mg) was added. After refluxing for 3 days, the reaction mixture
was cooled to room temperature and MeOH was evaporated. Then 150 mL of
CHCl3 and 60 mL of H2O were added, and the organic phase was separated. The
organic phase was washed with H2O (5 ꢂ 50 mL). After evaporation of the solvent,
the residue was hydrolyzed with 2 M NaOH in MeOH=H2O (80 mL, 4:1) at room
temperature for 12 h. Then MeOH was evaporated. H2O (70 mL) and CH2Cl2
(70 mL) were added to the residue. The organic phase was dispatched, and the aque-
ous phase was acidified with 37% HCl (pH 2). AcOEt (100 mL) was added to the
aqueous phase, and the organic phase was separated. The aqueous phase was again
extracted with AcOEt (2 ꢂ 60 mL), and the combined organic layers were dried over
Na2SO4. Evaporation of the solvent yielded 11 (3.66 g, 80%). White crystals. Mp
1
213–215 ꢀC (solidified, lit.[21] 214–216 ꢀC). H NMR (200 MHz, DMSO-d6): d 8.57
(d, J(1,3) ¼ 1.7 Hz, 1H, H-1), 8.24 (AB, d, J(3,4) ¼ 8.8 Hz, 1H, H-4), 7.98 (AB, dd,
J(3,4) ¼ 8.8 Hz, and J(1,3) ¼ 1.7 Hz, 1H, H-3), 7.67 (ABX, d, J(7,8) ¼ 8.3 Hz, 1H,
H-8), 7.53 (ABX, quasi t, J ¼ 8.0 Hz, 1H, H-7), 7.12 (ABX, d, J(6,7) ¼ 6.8 Hz, 1H,
H-6), 4.00 (s, methoxide, 3H); 3.38 (bs, OH). 13C NMR (50 MHz, DMSO-d6): d
169.2, 156.5, 135.0, 131.8, 130.4, 128.9, 128.5, 126.3, 123.7, 123.0, 108.4, 57.5.
5-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic Acid (12)
Small pieces of Na (2.27 g, 98.7 mmol) were added to a stirred solution of 11
(5.00 g, 24.75 mmol) in liquid NH3 (200 mL) and THF (50 mL) at ꢁ70 ꢀC for 1.5 h
under an N2 atmosphere. When the addition of Na was complete, the mixture was
stirred at the same temperature for 1 h. H2O (25 mL) in EtOH (40 mL) was added
to the reaction mixture dropwise for 1 h at the same temperature under N2 fumes.
After NH3 and EtOH were evaporated from the reaction mixture, ice (150 g) was
added to the mixture. The cold mixture was acidified with 37% aq. HCl (pH 3).
The aqueous layer was extracted with AcOEt (3 ꢂ 50 mL), and the combined organic
layers were dried over Na2SO4. The solvent was evaporated, and the residue was
crystallized from CHCl3=hexane to afford 4.60 g (90%) of 12. White crystals. Mp
147–149 ꢀC (lit.[22] 150–151 ꢀC). 1H NMR (400 MHz, CDCl3): d 11.60 (bs, 1H,
OH); 7.11 (quasi t, J ¼ 7.8 Hz, 1H, H-7), 6.74 (d, J(7,8) ¼ 7.8 Hz, 1H, H-8), 6.68 (d,
J(6,7) ¼ 8.2 Hz, 1H, H-6), 3.82 (s, methoxide, 3H), 3.08–2.90 (m, 3H), 2.79–2.71 (m,
1H), 2.60 (ddd, J ¼ 17.2 Hz, J ¼ 10.9 Hz, and J ¼ 6.2 Hz, 1H, H-2), 2.32–2.25 (m,
1H), 1.85 (dddd, J ¼ 17.2 Hz, J ¼ 13.2 Hz, J ¼ 11.3 Hz, and J ¼ 5.9 Hz, 1H, H-2).
13C NMR (100 MHz, CDCl3): d 181.5, 157.5, 136.2, 126.5, 124.8, 121.4, 107.5,
55.4, 39.7, 31.7, 25.6, 22.6.
Benzyl 5-Methoxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (13)
Diphenylphosphoryl azide (1.50 g, 5.4 mmol) and Et3N (0.60 g, 5.94 mmol)
were added to a stirred solution of 12 (1.00 g, 4.86 mmol) in anhydrous benzene

¨ ¨
N. OZTAS¸KIN, S. GOKSU, AND H. SEC¸ EN
2022
(40 mL). After the mixture was heated at reflux for 6 h, benzyl alcohol (1.57 g,
14.54 mmol) was added to the reaction mixture, and the solution was refluxed for
30 h. After the mixture was cooled to room temperature, the solvent was evaporated.
The residue was purified by column chromatograhy (SiO2, 20 g; hexane=AcOEt, 4:1)
to give 1.36 g (90%) of 13. Colorless solid. Mp 84–86 ꢀC (CHCl3=hexane). IR (KBr,
cmꢁ1): 3326, 3064, 3034, 2937, 2837, 1699, 1586, 1470, 1456, 1439, 1344, 1306, 1257,
1
1220, 1092, 1077, 913. H NMR (200 MHz, CDCl3): d 7.44–7.32 (m, aromatic, 5H);
7.12 (quasi t, J ¼ 7.8 Hz, 1H, H-7), 6.70 (br d, J ¼ 8.0 Hz, 2H, H-6, and H-8), 5.13 (s,
2H, OCH2), 4.88 (bs, 1H, NH), 4.06 (m, 1H, H-2), 3.84 (s, methoxide, 3H), 3.13 (dd,
2J ¼ 15.6 Hz, and 3J ¼ 4.7 Hz, 1H, H-1), 2.95–2.60 (m, 3H), 2.17–2.00 (m, 1H),
1.89–1.64 (m, 1H). 13C NMR (50 MHz, CDCl3): d 157.2 (CO), 155.8 (C-5), 136.6,
135.3, 128.5, 128.1 (2C), 126.5, 124.4, 121.6, 107.4, 66.6, 55.2, 46.4, 36.0, 28.4,
21.0. Elemental analysis calculated for C19H21NO3: C, 73.29; H, 6.80; N, 4.50.
Found: C, 73.24; H, 6.86; N, 4.40. EI-MS: 311.1 (Mþ, 1), 219.8 (28), 173.8 (20),
160.9 (25), 159.9 (75), 158.7 (100), 143.7 (28), 90.8 (65).
5-Methoxy-1,2,3,4-tetrahydronaphthalen-2-amine Hydrochloride (14)
Pd=C (60 mg) and 13 (0.50 g, 1.6 mmol) in MeOH (30 mL) and CHCl3 (1 mL,
for producing HCl) were placed in a 100-mL flask. A balloon filled with H2 gas
(3 L) was fitted to the flask. The mixture was deoxygenated by flushing with H2
and then hydrogenated for 24 h at room temperature. The catalyst was removed
by filtration. The evaporation of the solvent and recrystallization of the residue from
MeOH=Et2O resulted in 0.32 g (94%) of 14. Colorless solid. Mp 264–266 ꢀC (lit.[13a]
1
265–267 ꢀC). H NMR (400 MHz, D2O): d 7.03 (t, J ¼ 7.9 Hz, 1H, H-7), 6.68 (d,
J(7,8) ¼ 8.1 Hz, 1H, H-8), 6.64 (d, J(6,7) ¼ 7.8 Hz, 1H, H-6), 4.65 (bs, NHþ3 ), 3.64 (s,
2
3
methoxide, 3H), 3.37 (m, 1H, H-2), 2.97 (dd, J ¼ 16.1 Hz, and J ¼ 4.4 Hz, 1H,
H-1), 2.73–2.65 (m, 2H), 2.43 (ddd, J ¼ 14.3 Hz, J ¼ 10.3 Hz, and J ¼ 6.2 Hz, 1H),
2.04 (m, 1H), 1.64 (dddd, J ¼ 16.5 Hz, J ¼ 12.8 Hz, J ¼ 10.3 Hz, and J ¼ 5.9 Hz,
1H). 13C NMR (100 MHz, D2O): d 156.8, 133.8, 127.3, 123.6, 121.9, 109.0, 55.7,
47.2, 32.9, 22.2, 20.8.
ACKNOWLEDGMENTS
The authors are indebted to the Scientific and Technological Research Council
¨
of Turkey (TUBITAK, Grant No. 109T=241) and Ataturk University for their finan-
˙
¨
cial support of this work.
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