First synthesis of dopamine and rotigotin analogue 2-amino-6,8-dimethoxy-1, 2,3,4-tetrahydronaphthalene

Article abstract of DOI:10.1080/00397911.2013.841939

The title compound was synthesized starting from 3-(3,5-dimethoxyphenyl) acrylic acid in 11 steps with 30% total yield. The reaction sequence hydrogenation of acrylic acid, reduction of acid to alcohol derivative with LiAlH₄, reaction of alcohol with CBr₄/PPh₃, substitution reaction of alkyl halide to nitrile derivative with NaCN, hydrolysis of nitrile with NaOH, cyclization reaction of acid with PPA to give 1-tetralone, α-carboxylation of tetralone with Me₂CO ₃ in the presence of NaH, reduction of ketone group with Et ₃SiH, hydrolysis of ester, Curtius rearrangement of acid with diphenylphosphoryl azide followed by conversion to carbamate, and finally hydrogenolysis of carbamate afforded 2-amino-6,8-dimethoxy-1,2,3,4- tetrahydronaphthalene hydrogen chloride salt.

Full text of DOI:10.1080/00397911.2013.841939

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First Synthesis of Dopamine
and Rotigotin Analogue 2-
Amino-6,8-dimethoxy-1,2,3,4-
tetrahydronaphthalene
Süleyman Yılmaz a & Süleyman Göksu a
a Department of Chemistry, Faculty of Science , Atatürk University ,
Erzurum , Turkey
Accepted author version posted online: 08 Nov 2013.Published
online: 19 Mar 2014.
To cite this article: Süleyman Yılmaz & Süleyman Göksu (2014) First Synthesis of Dopamine
and Rotigotin Analogue 2-Amino-6,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:8, 1058-1065, DOI: 10.1080/00397911.2013.841939
To link to this article: http://dx.doi.org/10.1080/00397911.2013.841939
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Synthetic Communications1, 44: 1058–1065, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.841939
FIRST SYNTHESIS OF DOPAMINE AND
ROTIGOTIN ANALOGUE 2-AMINO-6,8-DIMETHOXY-1,
2,3,4-TETRAHYDRONAPHTHALENE
¨
Su¨leyman Yılmaz and Su¨leyman Goksu
Department of Chemistry, Faculty of Science, Atatu¨rk University, Erzurum,
Turkey
GRAPHICAL ABSTRACT
Abstract The title compound was synthesized starting from 3-(3,5-dimethoxyphenyl)acrylic
acid in 11 steps with 30% total yield. The reaction sequence hydrogenation of acrylic acid,
reduction of acid to alcohol derivative with LiAlH4, reaction of alcohol with CBr4/PPh3,
substitution reaction of alkyl halide to nitrile derivative with NaCN, hydrolysis of nitrile
with NaOH, cyclization reaction of acid with PPA to give 1-tetralone, a-carboxylation
of tetralone with Me2CO3 in the presence of NaH, reduction of ketone group with Et3SiH,
hydrolysis of ester, Curtius rearrangement of acid with diphenylphosphoryl azide
followed by conversion to carbamate, and finally hydrogenolysis of carbamate afforded
2-amino-6,8-dimethoxy-1,2,3,4-tetrahydronaphthalene hydrogen chloride salt.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords 2-Aminotetralin; Curtius rearrangement; dopamine; neurotransmitter;
rotigotin analogue; synthesis
INTRODUCTION
Monoamine hormone dopamine (1) is a neurotransmitter and is very
important in the central nervous system (CNS).[1] It has been reported that many
chemical compounds show dopaminergic activities.[2] Dopamine-like compounds,
especially 2-aminotetralin derivatives 2-amino-1,2,3,4-tetrahydronaphthalene-6,
7-diol (6,7-ADTN; 2),[3] 2-amino-1,2,3,4-tetrahydronaphthalene-5,6-diol (5,6-ADTN;
3),[4] and (S)-2-N,N-dipropylamino-1,2,3,4-tetrahydronaphthalen-5-ol (5-OH-DPAT,
Received July 25, 2013.
Address correspondence to Suleyman Go¨ksu, Department of Chemistry, Faculty of Science,
¨
Ataturk University, Erzurum 25240, Turkey. E-mail: sgoksu@atauni.edu.tr
¨
1058

DOPAMINE AND ROTIGOTIN ANALOGUE
1059
Figure 1. Dopamine (1), some selected dopaminergic compounds 1–5, and novel compound 6.
4),[5] are potential agonists at dopamine receptors. Dopamine agonist drug rotigotin
(5), commercially known as Neupro, is a derivative of 5-OH-DPAT (4). Rotigotin
(5) is used in the treatment of Parkinson’s disease[6] and restless legs syndrome[7] as
transdermal patch (Fig. 1).
In addition, 2-aminotetralin derivatives have some other beneficial biological
activities, including phenylethanolamine N-methyltransferase inhibition;[8] antifun-
gal activity;[9] 11b-hydroxylase inhibition;[10] a-adrenergic[11] melatonin-like
activity;[12] prolactin secretion inhibition;[13] antihypertensive,[14] sedative and anal-
gesic,[15] and 5-hydroxytryptaminergic activity,[16] AChE and MAO inhibition,[17]
GlyT1 inhibition,[18] B-Raf mutant tumor growth inhibition,[19] m-selective opioid
activity;[20] and pain management;[21] antihyperlipidemic, antiatherosclerotic,[22]
and seratonergic[23] activities. A lot of other biological activities of 2-aminotetralin
derivatives have been reported.
Because of the important biological activities of 2-aminotetralin derivatives, the
synthesis of novel dopamine analogues or convenient synthesis of known dopaminer-
gic compounds would be useful for further synthetic and biological purposes. For this
reason, we have already achieved the synthesis of 6,7-ADTN (2),[24] 5,6-ADTN (3),[25]
the main component of compound 4,[26] and some 2-aminoindane derivatives.[27]
It is well known that substituents on the phenyl rings of dopamine-related
compounds can lead to different selective biological activities against receptors.
Therefore, in the present study we focused on the first synthesis of potential biologi-
cally active 2-aminotetralin 6. The synthesis of 6 was accomplished starting from
3-(3,5-dimethoxyphenyl)acrylic acid (7) in 11 steps with an overall yield of 30%.
RESULTS AND DISCUSSION
The synthesis of the title compound was started from 3-(3,5-dimethoxyphenyl)
acrylic acid (7). 3-(3,5-Dimethoxyphenyl)propanoic acid (8) was synthesized via
Pd-C-catalyzed hydrogenation of compound 7 according to the procedure described
by Zhao et al.[28] The reduction of acid 8 with LiAlH4 gave 3-(3,5-dimethoxyphenyl)
propan-1-ol (9).[29] The conversion of 9 to nitrile 11 can be achieved by the reaction

¨
S. YILMAZ AND S. GOKSU
1060
of 9 with MsCl, PBr3=Et3N, or CBr4=PPh3 and then reacting the resulting product
with NaCN. Here, we saw that the latter procedure was the most convenient one.
Therefore, alcohol 9 was reacted with CBr4=PPh3 to give alkyl halide 10 according to
the procedure described by Jamie and Richards.[29c] Substitution reaction of 10 with
NaCN gave novel 4-(3,5-dimethoxyphenyl)butanenitrile (11) in good yield. Hydroly-
sis of 11 with 6 M NaOH at 78 ꢀC furnished 4-(3,5-dimethoxyphenyl)butanoic acid
(12)[30] by an alternative method. Polyphosphoric acid (PPA) prepared from
phosphoric acid and P2O5- catalyzed acylation or alkylation of aromatic compounds
have been used in the literature.[31] Following the same procedure, reaction of 12 with
PPA at 78 ꢀC yielded tetralone 13.[30a] Conversion of 1-tetralones to their a-carbonyl
derivatives with Me2CO3 in the presence of NaH has been given in the literature.[32]
Applying the same procedure to 13 gave a mixture of the desired new compound 14
and its tautomer 15. The mixture of 14 and 15 was reacted with Et3SiH in CF3CO2H
to give novel methyl 6,8-dimethoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate
Scheme 1. Synthesis of acid 17: (i) H2=Pd-C, THF, 25 ꢀC, 48 h, 95%; (ii) LiAlH4, THF, 0–25 ꢀC, 24 h, 88%;
(iii) CBr4=PPh3, CH3CN, 80 ꢀC, 2 h, 92%; (iv) NaCN, DMF, 50 ꢀC, 24 h, 85%; (v) 6 M NaOH, EtOH,
78 ꢀC, 24 h, then conc. HCl, 0 ꢀC, 90%; (vi) PPA prepared from P2O5=H3PO4, 80 ꢀC, 45 min., 90%; (vii)
Me2CO3=NaH, THF, 65 ꢀC, 24 h; (viii) Et3SiH, CF3CO2H, 72 ꢀC, 2.5 h, 80%; and (ix) 10% aqueous
NaOH, MeOH, 25 ꢀC, 24 h, then conc. HCl, 0 ꢀC, 87%.

DOPAMINE AND ROTIGOTIN ANALOGUE
1061
Scheme 2. Synthesis of dopamine and rotigotin analogue 19: (i) (PhO)2PON3=NEt3, C6H6, 80 ꢀC, 6 h, then
PhCH2OH, 80 ꢀC, 30 h, 85%; and (ii) H2=Pd-C, CHCl3-MeOH, 25 ꢀC, 24 h, 94%.
(16), which was hydrolyzed to corresponding acid derivative 17[32b] with a solution
of NaOH in H2O-MeOH and then acidified with dilute HCl (Scheme 1).
In our previous research, we have converted carboxylic acids to their carba-
mate derivatives via Curtius reaction of acids with diphenylphosphoryl azide
followed by addition of benzyl alcohol.[24–26] In a similar approach, the Curtius reac-
tion of 17 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 carbamate 18. Pd-C-catalyzed hydrogenolysis of 18 in the presence of
CHCl3 (for in situ production of HCl)[24–27] in MeOH gave novel dopamine analogue
6 as amine hydrochloride salt (19) in excellent yield (Scheme 2). The structures of all
1
synthesized compounds were characterized by H and 13C NMR. Nitrile and azide
functional groups were characterized by infrared (IR).
compound
In
summary,
the
title
2-amino-6,8-dimethoxy-1,2,3,
4-tetrahydronaphthalene (6) was synthesized as hydrochloride salt 19 from com-
mercially available 3-(3,5-dimethoxyphenyl)acrylic acid (7) in 11 steps and with
30% total yield for the first time. Because of the similar structure of compound 6
with other dopamine analogues, it may be very useful for further biological and
pharmacological purposes. In addition, 4-(3,5-dimethoxyphenyl)butanenitrile (11)
and benzyl 6,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (18) were
synthesized for the first time and carboxylic acid 12 was synthesized by an
alternative method.
EXPERIMENTAL
All chemicals and solvents are commercially available and were used after
distillation or treatment with drying agents. Melting points were determined on a
capillary melting apparatus (Buchi 530) and are uncorrected. IR spectra were
obtained from solutions in 0.1-mm cells with a Perkin-Elmer spectrophotometer.
The 1H and 13C NMR spectra were recorded on 400- (100-) MHz Varian and Bruker
spectrometers with d in ppm and Me4Si as the internal standard. Elemental analyses
were performed on a Leco CHNS-932 apparatus. All column chromatography

¨
S. YILMAZ AND S. GOKSU
1062
was performed on silica gel (60 mesh, Merck) using preparative thick-layer
chromatography (PLC) and 1 mm of silica gel 60 PF (Merck) on glass plates.
Acid 8,[28] alkyl halide 10,[29c] and tetralone 13[30a] were synthesized according
to the literature procedure.
4-(3,5-Dimethoxyphenyl)butanenitrile (11)
NaCN (1.08 g, 22.02 mmol) was added to a solution of alkyl bromide 10
(1.90 g, 7.34 mmol) in DMF (25 ml) at 50 ꢀC. The reaction mixture was stirred at
the same temperature for 24 h. After the mixture was cooled to room temperature,
EtOAc (80 ml) and H2O (20 ml) were added to this mixture. The organic layer was
separated and extracted with H2O (3 ꢁ 20 ml). The organic phase was dried over
Na2SO4 and the solvent was evaporated. Chromatography of the residue on a
silica-gel column (30 g) with 30% EtOAc–hexane gave colorless liquid nitrile 11
(1.28 g, 85%). 1H NMR (400 MHz, CDCl3) d 6.33 (s, 3H, Ar-H), 3.77 (s, 6H,
2OCH3), 2.71 (t, 2H, CH2, J ¼ 7.4 Hz), 2.31 (t, 2H, CH2, J ¼ 7.4 Hz), 1.96 (quintet,
2H, CH2, J ¼ 7.4 Hz). 13C NMR (100 MHz, CDCl3) d 161.22 (2C), 142.30 (C), 119.80
(CN), 106.41 (2CH), 98.50 (CH), 55.52 (2OCH3), 34.84 (CH2), 26.94 (CH2), 16.59
(CH2). IR (CH2Cl2, cmꢂ1): 3001, 2939, 2840, 2246, 1732, 1597, 1463, 1430, 1349,
1325, 1294, 1255, 1205, 1154, 1071, 940. Anal. calcd. for C12H15NO2: C, 70.22; H,
7.37; N, 6.82. Found: C, 70.18; H, 7.39; N, 6.80.
Methyl 6,8-Dimethoxy-1,2,3,4-tetrahydronaphthalene-2-
carboxylate (16)
NaH (0.35 g, 14.6 mmol) and a solution of Me2CO3 (1.31 g, 14.6 mmol) in dry
THF (10 ml) were added to a stirred solution of ketone 13 (1.20 g, 5.83 mmol) in dry
THF (30 ml) under N2(g) at rt. The mixture was refluxed for 24 h under N2(g). After
AcOH (2 ml) was added to the cooled reaction mixture, most THF was evaporated.
CH2Cl2 (60 ml) and a solution of Na2CO3 (50 ml) were added to the residue. The
organic layer was separated and washed with Na2CO4 (2 ꢁ 30 ml) and H2O
(30 ml). After drying over Na2SO4 and evaporation of CH2Cl2, column chromato-
graphy of the residue on silica gel (30 g) with 30% EtOAc–hexane afforded an insep-
arable mixture of 14 and 15, which were directly converted to 16 without further
characterization. CF3CO2H (10 ml) and Et3SiH (1.43 g, 12.31 mmol) were added to
a mixture of 14 and 15 (1.30 g, 4.92 mmol). The reaction mixture was refluxed for
2.5 h under N2(g). The reaction mixture was cooled to rt and CF3CO2H was evapo-
rated. Concentrated NaHCO3 solution in H2O (40 ml) and EtOAc (40 ml) were
added to the residue, and the organic layer was separated. The H2O phase was
extracted with EtOAc (2 ꢁ 40 ml) and the combined organic layers were washed with
H2O (30 ml). Organic phase was dried over Na2SO4, and the solvent was evaporated
under reduced pressure. Oily compound 16 was obtained by eluting of the residue on
1
a silica-gel column with 5%, 10%, and 30% EtOAc–hexane (1.16 g, 80% yield). H
NMR (400 MHz, CDCl3) d 6.29 (d, 1H, Ar-H, J ¼ 2.0 Hz), 6.2 (d, 1H, Ar-H,
J ¼ 2.0 Hz), 3.79 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.73 (s, 3H, OCH3),
3.08–2.96 (m, 1H), 2.82–2.78 (m, 2H), 2.70–2.64 (m, 2H), 2.20–2.13 (m, 1H), 1.80
(dddd, 1H, 3J ¼ 6.9, 3J ¼ 10.8, 3J ¼ 12.4, 2J ¼ 17.7 Hz). 13C NMR (100 MHz, CDCl3)

DOPAMINE AND ROTIGOTIN ANALOGUE
1063
d 176.4 (CO), 158.7 (C), 158.5 (C), 137.7 (C), 116.5 (C), 104.2 (CH), 96.2 (CH), 55.4
(2C, OCH3), 51.9 (OCH3), 40.1 (CH), 29.4 (CH2), 25.8 (CH2), 25.5 (CH2). IR
(CH2CI2, cmꢂ1): 3006, 2996, 2949, 2839, 1735, 1609, 1596, 1492, 1458, 1436, 1360,
1342, 1301, 1273, 1256, 1236, 1196, 1170, 1148, 1105, 1052, 1027, 1052, 1027, 962,
937. Anal. calcd. for C14H18O4: C, 67.18; H, 7.25. Found: C, 67.12; H, 7.28.
Benzyl 6,8-Dimethoxy-1,2,3,4-tetrahydronaphthalen-2-
ylcarbamate (18)
Diphenylphosphoryl azide (2.80 g, 10.16 mmol) and Et3N (1.03 g, 10.16 mmol)
were added to a stirred solution of acid 17 (2.00 g, 8.47 mmol) in anhydrous benzene
(40 ml) at rt. The mixture was heated at reflux temp for 6 h. Benzyl alcohol (2.75 g,
25.41 mmol) was added to the reaction mixture, and it was refluxed for 30 h. After
the mixture was cooled to rt, the solvent was evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel (40 g) with 20%
EtOAc–hexane. The latest solid was crystallized with EtOAc–hexane, and carbamate
1
18 was obtained as white crystals (2.46 g, 85% yield). Mp 129–131 ꢀC. H NMR
(400 MHz, CDCl3): d 7.37–7.30 [m, 5H, Ar-H, (Ph)], 6.28 (d, 1H, Ar-H, J ¼ 2.2 Hz),
6.23 (d, 1H, Ar-H, J ¼ 2.2 Hz), 5.11 (s, 2H, OCH2), 4.84 (d, 1H, NH, J ¼ 7.1 Hz),
4.05–3.96 (m, 1H, CH), 3.78 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.00 (A part of
2
3
AB, dd, 1H, J ¼ 16.7, J ¼ 5.2 Hz), 2.85–2.81 (m, 2H), 2.38 (B part of AB, dd,
1H, 2J ¼ 16.7, 3J ¼ 8.2 Hz), 2.06–2.00 (m, 1H), 1.82–1.68 (m, 1H). 13C NMR
(100 MHz, CDCl3): d 160.0 (CO), 158.7 (C), 156.0 (C), 137.5 (C), 136.9 [CH (Ph)],
128.8 [3CH (Ph)], 128.3 [2CH (Ph)], 115.6 (C), 104.2 (CH), 96.3 (CH), 66.8
(OCH2), 55.53 (OCH3), 55.47 (OCH3), 47.0 (CH), 29.7 (CH2), 28.9 (CH2), 28.0
(CH2). IR (CH2CI2, cmꢂ1): 3684, 3317, 2943, 2880, 2838, 1692, 1595, 1519, 1493,
1455, 1424, 1342, 1306, 1271, 1212, 1194, 1147, 1097, 1050, 934. Anal. calcd. for
C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C, 70.35; H, 6.80; N, 4.13.
2-Amino-6,8-dimethoxy-1,2,3,4-tetrahydronaphthalene
Hydrogen Chloride (19)
Pd=C (80 mg) and carbamate 18 (2.00 g, 5.87 mmol) in MeOH (60 ml) and
CHCl3 (4 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. The mixture was hydrogenated for 24 h at rt. After the catalyst was removed by
filtration, evaporation of the solvent and recrystallization of the residue from
MeOH-Et2O afforded amine hydrochloride salt 19 (1.86, 94% yield). Colorless solid.
Mp 280–282 ꢀC. 1H NMR (400 MHz, D2O): d 6.30 (s, 1H, Ar-H), 6.27 (s, 1H, Ar-H),
4.65 (bs, 3H of NH3 and H2O of D2O), 3.66 (s, 3H, OCH3), 3.64 (s, 3H, OCH3),
3.45–3.37 (m, 1H, CH), 2.93 (dd, 1H, 2J ¼ 16.4 Hz, 3J ¼ 5.5 Hz), 2.73–2.69 (m,
2H), 2.36 (dd, 1H, 2J ¼ 16.4, 3J ¼ 9.6 Hz), 2.06–1.98 (m, 1H), 1.66 (dddd, 1H,
3J ¼ 7.5, 3J ¼ 10.3, 3J ¼ 12.2, 2J ¼ 17.3 Hz). 13C NMR (100 MHz, D2O): d 158.5
(C), 158.1 (C), 137.3 (C), 113.9 (C), 105.0 (CH), 96.6 (CH), 55.7 (OCH3), 55.5
(OCH3), 47.6 (CH), 27.0 (CH2), 26.8 (CH2), 26.4 (CH2). Anal. calcd. for
C12H18ClNO2: C, 59.14; H, 7.44; N, 5.75. Found: C, 59.10; H, 7.47; N, 5.74.

¨
S. YILMAZ AND S. GOKSU
1064
FUNDING
The authors are indebted to the Scientific and Technological Research Council of
¨
Turkey (TUBITAK, Grant No. 109 T=241) and Ataturk University for financial
˙
¨
support of this work.
SUPPORTING INFORMATION
1
Full experimental detail and H and 13C NMR spectra can be found via the
‘‘Supplementary Content’’ section of this article’s Web page.
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