A Concise Synthesis of 2-Amino-1,2,3,4-tetrahydronaphthalene-6,7-diol ('6,7-ADTN') from Naphthalene-2,3-diol

Article abstract of DOI:10.1002/hlca.200390272

2-Amino-1,2,3,4-tetrahydronaphthalene-6,7-diol (2; 6,7-ADTN) was synthesized starting from naphthalene-2,3-diol in seven steps and with an overall yield of 44%. Methylation of naphthalene-2,3-diol with dimethyl sulfate, followed by Friedel-Crafts acylatio

Full text of DOI:10.1002/hlca.200390272

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Helvetica Chimica Acta Vol. 86 (2003)
A Concise Synthesis of 2-Amino-1,2,3,4-tetrahydronaphthalene-6,7-diol
(−6,7-ADTN×) from Naphthalene-2,3-diol
by S¸leyman Gˆksu, Cavit Kazaz, YasÀar S¸tbeyaz*, and Hasan SeÁen*
Department of Chemistry, Faculty of Arts and Sciences, Atat¸rk University, TR-25240 Erzurum
2-Amino-1,2,3,4-tetrahydronaphthalene-6,7-diol (2; 6,7-ADTN) was synthesized starting from naphtha-
lene-2,3-diol in seven steps and with an overall yield of 44%. Methylation of naphthalene-2,3-diol with dimethyl
sulfate, followed by FriedelÀCrafts acylation with AcCl, gave 2-acetyl-6,7-dimethoxynaphthalene. 2-Acetyl-6,7-
dimethoxynaphthalene was converted to 6,7-dimethoxynaphthalene-2-carboxylic acid by a haloform reaction.
Birch reduction of the carboxylic acid with 4 mol-equiv. of Na in liquid ammonia afforded 1,2,3,4-tetrahydro-6,7-
dimethoxynaphthalene-2-carboxylic acid, from which 2 was obtained by a Curtius reaction, followed by
hydrogenolysis and demethylation.
Introduction.
Dopamine (1) [1], a hormone-like substance, is an important
neurotransmitter. When present in normal quantities, it facilitates critical brain
functions. 2-Amino-1,2,3,4-tetrahydronaphthalene-6,7-diol (ˆ−2-amino-6,7-dihydroxy-
1,2,3,4-tetrahydronaphthalene×, 6,7-ADTN; 2) is a compound suggested to act as a
potential agonist at the dopamine receptors [2] and to stimulate helix dopamine
receptors [3]. It also has a strong central stimulant action [4] and is as active as
dopamine in producing adenylate cyclase activity [5][6]. It has been suggested that 6,7-
ADTN (2) interacts with the dopamine receptor with slightly greater affinity than
dopamine itself [7].
Thrift [8a], starting from veratrol, performed the first synthesis of 6,7-ADTN (2)1).
Cannon et al. [9] described the second method for the preparation of 2 starting from
ethyl 3-(3,4-dimethoxyphenyl)propanoate. Horn et al. [10] developed a procedure for
the synthesis of 2 starting from (3,4-dimethoxyphenyl)acetic acid. Narula and Schuster
[11] synthesized 2 from 2-(3,4-dimethoxyphenyl)ethanol via functionalized aryllithium
reagents. Nordlander et al. [12] developed the first asymmetric synthesis of (R)-6,7-
ADTN by using veratrol and d-aspartic acid. (R)-1,2,3,4-tetrahydro-6,7-dimethoxy-
naphthalene-2-amine, O-methylated 6,7-ADTN, was synthesized by Charlton et al. [13]
starting from 2-amino-4,5-dimethoxybenzoic acid. These syntheses of 2 were per-
formed in 5 9 steps with overall yields ranging from 12to 52%. In this paper, we report
a convenient synthesis of 6,7-ADTN (2) with a moderate overall yield (44%) starting
1
)
For a modified synthesis, see [8b].

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from naphthalene-2,3-diol (3), a commercially available naphthalene derivative, which
was used in the synthesis of 2 for the first time (Scheme).
Scheme
i) Me2SO4, K2CO3, acetone, reflux; 94%. ii) AcCl, AlCl3, 1,2-dichloroethane, 08; 88%. iii) Br2, NaOH, then 6m
HCl, 90%. iv) Na, liq. NH3, then 37% HCl; 90%. v) (PhO)2P(O)N3, Et3N, C6H6, reflux; then PhCH2OH, reflux;
86%. vi) H2, Pd-C, EtOH, CHCl3; 96%. vii) 48% HBr, reflux; 80%.
Results and Discussion. The synthesis started with naphthalene-2,3-diol (3).
Methylation of 3 with Me2SO4 in the presence of K2CO3 gave 2,3-dimethoxynaph-
thalane (4). Our literature search showed that the FriedelÀCraft acetylation of 4 has
been performed by reacting with AcCl in PhNO2 to give 1-(6,7-dimethoxynaphthalen-
2-yl)ethanone (5) [14][15]. Despite moderate yields, these procedures involve some
difficulties related to the removal of solvent and a series of workup procedures.
Another procedure [16], again performed in PhNO2 with Ac2O, gave 5 in low yield.
Our method for the preparation of 5 was to react 4 with AcCl in 1,2-dichloroethane.
Thus, this simple method gave 5 in high yield. Acetyl compound 5 was converted to
carboxylic acid 6 by a haloform reaction (Br2/NaOH). The most critical step of our
synthesis was the Birch reduction of 6,7-dimethoxynaphthalene-2-carboxylic acid (6).
We assume that the Birch reaction of 6 proceeded by the reduction of the electron-
deficient ring of 6. Indeed, the reaction of 6 with 4 mol.-equiv. of Na in liquid NH3
afforded tetrahydronaphthalene derivative 7 in high yield (90%). The conversion of
the carboxylic acid 7 to carbamate 8 was performed by a known procedure via Curtius
rearrangement, followed by treatment with PhCH2OH. Hydrogenolysis of 8 in MeOH
in the presence of CHCl3 gave a pure dimethoxy derivative of 6,7-ADTN hydro-
chloride 9 as the sole product. The demethylation of 9 to hydrobromide of 6,7-ADTN,
10, was performed as described in the literature.
In summary, with relatively little synthetic effort, we have achieved a concise
synthesis of 6,7-ADTN (2) in seven steps starting from commercially available
naphthalane-2,3-diol (3) (overall yield of 44%).

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Helvetica Chimica Acta Vol. 86 (2003)
Experimental Part
General. Column chromatography (CC): silica gel (60 mesh, Merck). Prep. thick-layer chromatography
(PLC): 1-mm of silica gel 60 PF (Merck) on glass plates. M.p.: Thomas-Hoover cap. melting-point apparatus;
uncorrected. IR Spectra: from solns., 0.1-mm cells, with a Perkin-Elmer spectrophotometer. 1H- and 13C-NMR
spectra: 200 (50)-MHz Varian spectrometer; d in ppm.
2,3-Dimethoxynaphthalene (4). A 500-ml, three-necked flask fitted with a condenser and a 50-ml dropping
funnel was charged with anh. K2CO3 (38 g, 275 mmol), 300 ml of acetone, and naphthalene-2,3-diol (3; 2 0 g,
125 mmol). Me2SO4 (34.6 g, 26.6 ml, 275 mmol) was added under stirring from the dropping funnel to the
mixture over a period of 2min. The mixture warmed appreciably and began to reflux after an additional 5 min.
When the spontaneous boiling subsided (15 20 min after the addition of the Me2SO4), the stirred mixture was
heated gently under reflux for 15 h. The precipitate was filtered off, and the acetone was evaporated. The
residue was dissolved in CH2Cl2, and the soln. was washed with H2O (2 Â 40 ml) and dried (Na2SO4). Removing
the solvent under reduced pressure gave 4 (22.2 g, 94%). White solid. M.p. 110 112o (CH2Cl2/hexane; [15]:
113 116o). 1H-NMR (200 MHz, CDCl3): 7.70 (AA' of AA'BB', 2 H); 7.34 (BB' of AA'BB', 2 H); 7.13 (s, 2 H);
4.00 (s, 6 H). 13C-NMR (50 MHz, CDCl3): 151.5; 131.2; 128.3; 126.2; 108.3; 57.8.
1-(6,7-Dimethoxynaphthalene-2-yl)ethanone (5). To a stirred soln. of 4 (22 g, 117.0 mmol) in 350 ml of dry
1,2-dichloroethane was added freshly distillated AcCl (11.0 g, 140.1 mmol) in one portion and AlCl3 (42.0 g,
315 mmol) in small portions over 1 h at 0o. The mixture was stirred for 12h at 0 o, and then 300 g of ice and 100 ml
of conc. HCl were added. The org. phase was separated, and the aq. phase was extracted with CH2Cl2 (2 Â
150 ml). The org. phases were combined and dried (Na2SO4). Evaporation of the solvents and chromatography
of the residue through a short silica-gel column (10 g; CH2Cl2) gave 5 (23.7 g, 88%). White crystals. M.p.104
106o (EtOH; [15]: 104 106o). 1H-NMR (200 MHz, CDCl3): 8.20 (br. s, 1 H); 7.76 (A of AB, dd, J ˆ 8.5, 1.3, 1 H);
7.59 (B of AB, br. d, J ˆ 8.5, 1 H); 7.08 (s, 1 H); 7.00 (s, 1 H); 3.91 (s, 6 H); 2 .59 (s, 3 H). 1H-NMR: in agreement
with the data given in [16]. 13C-NMR (50 MHz, CDCl3): 199.8; 153.5; 152.0; 135.0; 133.9; 130.3; 128.5; 124.6;
109.5; 108.0; 57.8 (2 C); 28.2.
6,7-Dimethoxynaphthalene-2-carboxylic Acid (6). To a stirred soln. of NaOH (34.89 g, 870 mmol) in 120 ml
of H2O was added Br2 (42.6 g, 266.2 mmol) over 30 min at 0o. To this mixture was added a soln. of 5 (20.00 g,
87.0 mmol) in 60 ml of THF slowly over 30 min at 0o. The mixture was warmed to r.t. and stirred for 8 h. The org.
phase was separated in a separatory funnel and dispatched. To the aq. soln. were added ice (200 g) and 20%
NaHSO3 soln. (100 ml). After acidification of the aq. soln. with 37% HCl (pH ꢀ 3), the solidified acid 6 was
filtered with suction and dried at 60o (18.2 g, 90%). White crystals, solidified. M.p. 238 240o ([15]: 240 243o).
1H-NMR (200 MHz, (D6)DMSO): 12.65 (br. s, 1 H); 8.42(br. s, 1 H); 7.79 (m, 2 H); 7.48 (s, 1 H); 7.36 (s, 1 H);
3.90 (s, 3 H); 3.89 (s, 3 H). 13C-NMR (50 MHz, (D6)DMSO): 169.5; 152.9; 151.6; 133.2; 130.6; 129.8; 128.1;
127.8; 125.3, 109.5; 108.1; 57.4 (2 C).
1,2,3,4-Tetrahydro-6,7-dimethoxynaphthalene-2-carboxylic Acid (7). To
a stirred soln. of 6 (10 g,
43.1 mmol) in 300 ml of liq. NH3 at À70o were added small thinly cut pieces of Na (4.0 g, 174.0 mmol) over
1 h under N2 atmosphere. The mixture was additionally stirred for 1 h at the same temp. Then, 20 ml of H2O in
30 ml of EtOH was added dropwise over 1 h under N2. After the NH3 and EtOH were evaporated, ice (100 g)
was added. After acidification of the aq. soln. with 37% HCl (pH ꢀ 3), the solidified acid 7 was filtered with
suction and dried at 40o (9.2g, 90%). White crystals. M.p. 135 137 o (CH2Cl2/hexane; [17]: 136.5 137.5o).
1H-NMR (200 MHz, CDCl3): 11.76 (br. s, 1 H); 6.58 (s, 1 H); 6.57 (s, 1 H); 3.83 (s, 6 H); 3.01 2.93 (m, 2 H);
1
2.89 2.68 (m, 3 H); 2.26 2.18 (m, 1 H); 1.95 1.75 (m, 1 H). H-NMR: in agreement with the data given in
[13]. 13C-NMR (50 MHz, CDCl3): 183.8; 149.4; 149.3; 129.4; 128.4; 114.0; 113.8; 57.9 (2C); 41.9, 32.9; 30.0; 27.7.
Benzyl N-(1,2,3,4-Tetrahydro-6,7-dimethoxynaphthalene-2-yl)carbamate (8). Carbamate 8 was prepared
from 7 according to the procedure described by Charlton et al. [13] in a yield of 86%. M.p. 123 125o ([13]: 130
131.5o). 1H-NMR (200 MHz, CDCl3): 7.34 (m, 5 H); 6.56 (s, 1 H); 6.51 (s, 1 H); 5.09 (br. s, 2H); 5.02( d, J ˆ 8,
1 H); 4.00 (m, 1 H); 3.82( s, 6 H); 3.01 (dd, J ˆ 16.2, 4.5, 1 H); 2.81 2.76 (m, 2H); 2.56 ( dd, J ˆ 16.2, 8.0, 1 H);
2.05 1.99 (m, 1 H); 1.79 1.69 (m, 1 H). 1H-NMR: in agreement with the data given in [13]. 13C-NMR
(50 MHz, CDCl3): 157.8; 149.6; 149.4; 138.6; 130.5; 130.1, 129.3; 128.9; 127.8; 114.3; 113.7; 68.6; 57.9 (2 C); 48.9;
37.5; 30.9; 28.7.
2-Amino-1,2,3,4-tetrahydro-6,7-dimethoxynaphthalene Hydrochloride (9). By a little modification, the
procedure described in [18] for the reduction of 4-azido-3-hydroxybutanenitrile was applied to 8 to give 9. Into a
100-ml flask were placed Pd/C (50 mg) and 8 (0.50 g, 1.47 mmol) in MeOH (30 ml) and CHCl3 (1 ml). A balloon
filled with H2 gas (3 l) was fitted to the flask. The mixture was deoxygenated by flushing with H2 and then
hydrogenated for 24 h at r.t. The catalyst was removed by filtration. Concentration gave 9 (0.34 g, 95%). Beige

Helvetica Chimica Acta Vol. 86 (2003)
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solid. M.p. 217 219o (MeOH/Et2O; [8]: 220 221o). 1H-NMR (200 MHz, D2O): 6.62( s, 2H); 3.67 ( s, 3 H); 3.66
(s, 3 H); 3.64 3.40 (m, 1 H); 2 .96 (dd, J ˆ 16.1, 4.8, 1 H); 2.73 2.60 (m, 3 H); 2.12 2.02 (m, 1 H); 1.81 1.66
1
(m, 1 H). H-NMR: in agreement with the data given in [13]. 13C-NMR (50 MHz, D2O): 151.4; 151.1; 132.0;
129.0; 116.8; 116.4; 60.3 (2 C); 52.1; 36.8; 31.1; 30.3.
2-Amino-1,2,3,4-tetrahydronaphthalene-6,7-diol Hydrobromide (10). This compound was prepared from 9
by the procedure described by Cannon et al. [9] in a yield of 80%. M.p. 267 269o (MeOH/Et2O; [8]: 270 271o).
1H-NMR (200 MHz, D2O): 6.48 (s, 2H); 3.45 3.31 ( m, 1 H); 2 .85 (dd, J ˆ 16.1, 4.8, 1 H); 2.62 2.49 (m, 3 H);
2.06 1.97 (m, 1 H); 1.74 1.58 (m, 1 H). 13C-NMR (50 MHz, D2O): 146.8; 146.5; 131.3; 128.4; 120.3, 119.9; 51.9;
36.4; 31.0; 30.0.
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Received May 31, 2003