Highly efficient synthesis and chemical separation of 5-amino- and 7-amino-4-hydroxy-2-naphthoic acids

Article abstract of DOI:10.1016/j.tetlet.2007.05.040

5-Amino- and 7-amino-4-hydroxy-2-naphthoic acids were synthesized for the first time via a microwave-assisted pathway. The separation of the two isomers was then conveniently achieved by exploiting their different reactivities with CDI.

Full text of DOI:10.1016/j.tetlet.2007.05.040

Tetrahedron Letters 48 (2007) 4653–4655
Highly efficient synthesis and chemical separation of
5-amino- and 7-amino-4-hydroxy-2-naphthoic acids
Sabrina Castellano, Ciro Milite, Pietro Campiglia and Gianluca Sbardella*
`
Dipartimento di Scienze Farmaceutiche, Universita degli studi di Salerno, Via Ponte Don Melillo, Fisciano 84084, Italy
Received 2 April 2007; revised 30 April 2007; accepted 9 May 2007
Available online 16 May 2007
Abstract—5-Amino- and 7-amino-4-hydroxy-2-naphthoic acids were synthesized for the first time via a microwave-assisted
pathway. The separation of the two isomers was then conveniently achieved by exploiting their different reactivities with CDI.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Aminonaphthol sulfonic acids,1 as 7-amino-4-naphthol-
2-sulfonic acid (J acid, Fig. 1) and 5-amino-4-naphthol-
2-sulfonic acid (H monoacid, Fig. 1), have been widely
used as intermediates in the manufacture of direct dyes
(dyes used without mordant) for a long time.2 In addi-
tion to this application, they recently also emerged as
synthetic intermediates for a number of biologically
active compounds and pharmaceutical candidates.3–9
amino-4-hydroxy-2-naphthoic acid 1a (Fig. 1) are
reported.10,11 Moreover, to the best of our knowledge,
there is no literature report of the synthesis of 5-amino-
4-hydroxy-2-naphthoic acid 1b. Thus we decided to set
up a convenient single method for the synthesis of both
these building blocks.
In this work we describe, for the first time, the prepara-
tion of compounds 1a and 1b and their successful
separation.
As part of a project aimed at discovering novel small-
molecule inhibitors of arginine methyltransferases,9 we
were interested in the synthesis of the carboxy- ana-
logues of the aminonaphthol sulfonic acids. We then
realized that, while a successful pathway leading to the
preparation of 6-amino-4-hydroxy-2-naphthoic acid
was described,4 only failed attempted syntheses of 7-
As nitrobenzaldehydes are reported to resinify under
alkaline Stobbe conditions,12 we used a Wittig reaction
between 3-nitrobenzaldehyde and carboxyphosphorane
213 to regioselectively14 prepare the (E)-nitrophenylitac-
onate 3,12,15 which was selectively reduced with zinc dust
in acetic acid to amino derivative 4 (Scheme 1).16 The
OH
OH NH2
CHO Ph3P
+
COOMe
COOH
COOMe
COOH
a
HO3S
NH2
HO3S
NO2
X
J acid
OH
H monoacid
OH NH2
2
3; X= NO2
4; X= NH2
b
COOH
H2N
COOH
+
c, d
HOOC
NH2
HOOC
1a
1b
NH2 OH
OH
1a (HCl), 1b (HCl); 1:2
Figure 1. J acid, H monoacid and their carboxy- analogues 1a and 1b.
Scheme 1. Reagents and conditions: (a) benzene, rt, 24 h; (b) Zn
(6 mol equiv), AcOH, rt, 24 h; (c) AcONa (1.5 mol equiv), Ac2O, MW
(300 W, 5 min); (d) HCl 8 N, 5 h.
*
Corresponding author. Tel.: +39 089 96 9770; fax: +39 089 96
9602; e-mail: gsbardella@unisa.it
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.040

4654
S. Castellano et al. / Tetrahedron Letters 48 (2007) 4653–4655
COOR
H2N
COOEt
+
COOEt
subsequent ring closure via Friedel–Crafts acylation was
successfully performed by using a single-mode micro-
wave irradiation17 at a constant irradiation power dur-
ing a short reaction time (1.5 equiv NaOAc, Ac2O,
300 W, 5 min).18 Hydrolysis of the crude furnished a
mixture of title acids 1a and 1b (1:2 ratio, determined
by NMR) in a satisfactory 70% overall yield, without
intentional purification of the intermediates.19
b
H2N
a
OH
OH
HN
O
O
1a, 1b; R = H
5a, 5b; R = Et
5a (33 %)
6 (55 %)
c
c
H2N
COOH
COOH
With the mixture of the two isomeric acids in our hands,
we turned our attention to their separation. As a matter
of fact, accordingly to what was previously reported for
similar derivatives,10,11 this task revealed to be not easy.
After the failure of fractionated crystallization and both
conventional and flash chromatography (data not
shown), we were able to separate the mixture only
through analytical RP-HPLC (Fig. 2).20
+
NH2 OH
1b (HCl)
OH
1a (HCl)
Scheme 2. Reagents and conditions: (a) EtOH, H2SO4, reflux, 24 h; (b)
CDI, THF, 0 ꢁC, 3 h; (c) HCl 8 N, 5 h.
Unfortunately, this result was not reproducible on a pre-
parative scale (preparative RP-HPLC, same conditions,
data not shown). For this reason we decided to investi-
gate if the expected difference in reactivity resulting from
the relative positions of the amino and the hydroxy
group in the two compounds could be exploited for their
separation. Actually, the reaction21 of the mixture of
ethyl esters 5a and 5b (from 1a and 1b, respectively) with
CDI in THF at 0 ꢁC for 3 h converted 5b22 into the cyc-
lic carbamate 6 (Scheme 2), leaving 5a unreacted (33%
and 55% yield, respectively). The two derivatives were
easily separated by double extraction and then quantita-
tively converted into acids 1a and 1b by hydrolysis with
8 N hydrochloric acid.
the drug discovery process as well of intermediates in
the manufacture of dyes.
Acknowledgments
Dr. Assunta Napolitano is kindly acknowledged for
mass spectra. Dr. Ludovic Boully and Dr. Abdellah
Yamani are kindly acknowledged for helpful critical dis-
cussion. Financial support was provided by grants from
Regione Campania 2003, LR 5/02, Ministero dell’Uni-
`
versita e della Ricerca Scientifica e Tecnologica (PRIN
`
2005), and Universita di Salerno, Italy.
In conclusion, we have developed a convenient pathway
leading to the first synthesis of 5-amino- and 7-amino-4-
hydroxy-2-naphthoic acids. An efficient microwave-as-
sisted transformation, together with a relatively straight-
forward separation process exploiting the different
chemical reactivities of the two isomers, makes this pro-
tocol useful for the preparation of building blocks for
References and notes
1. For the nomenclature of aminonaphthol sulfonic acids
see: de Barry Barnett, E. Chem. News J. Ind. Sci. 1921,
123, 33.
2. Fierz-David, H. E.; Blangey, L. Fundamental Processes of
Dye Chemistry; Interscience: New York, 1949.
3. Maurer, K.; Tang, A. H.; Kenyon, G. L.; Leavitt, A. D.
Bioorg. Chem. 2000, 28, 140–155.
4. Duffy, K. J.; Price, A. T.; Delorme, E.; Dillon, S. B.;
Duquenne, C.; Erickson-Miller, C.; Giampa, L.; Huang,
Y.; Keenan, R. M.; Lamb, P.; Liu, N.; Miller, S. G.;
Rosen, J.; Shaw, A. N.; Smith, H.; Wiggall, K. J.; Zhang,
L.; Luengo, J. I. J. Med. Chem. 2002, 45, 3576–3578.
5. Jenkins, J. L.; Shapiro, R. Biochemistry 2003, 42, 6674–
6687.
6. Banfi T.; Beatriz M.; Gimenez Gallego, G.; Valverde
Lopez, S.; Lozano Puerto, R. M.; Cuevas Sanchez, P. PCT
Int. Appl. WO 2004078704, 2004; Chem. Abstr., 2004 141,
277372.
7. Cheng, D.; Yadav, N.; King, R. W.; Swanson, M. S.;
Weinstein, E. J.; Bedford, M. T. J. Biol. Chem. 2004, 279,
23892–23899.
8. Manetti, F.; Tintori, C.; Armand-Ugon, M.; Clotet-
Codina, I.; Massa, S.; Ragno, R.; Este, J. A.; Botta, M.
J. Chem. Inf. Model. 2006, 46, 1344–1351.
1b
800
600
400
200
0
800
600
400
200
0
1a
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.5 35.0
9. Ragno, R.; Simeoni, S.; Castellano, S.; Vicidomini, C.;
Mai, A.; Caroli, A.; Tramontano, A.; Bonaccini, C.;
Trojer, P.; Bauer, I.; Brosch, G.; Sbardella, G. J. Med.
Chem. 2007, 50, 1241–1253.
10. Hopper, I. V.; Syme, A. C.; Wilson, F. J. J. S. D. C. 1942,
58, 93–97.
Minutes
Figure 2. Analytical RP-HPLC separation of isomers 1a and 1b was
performed on C18 column (Vydac 218TP152010) using a gradient of
acetonitrile (40–70% acetonitrile in 30 min) in 0.1% aqueous TFA at
1 mL/min.

S. Castellano et al. / Tetrahedron Letters 48 (2007) 4653–4655
4655
11. Beech, W. F.; Legg, N. J. Chem. Soc. 1950, 961–966.
12. Awad, W. I.; Kandile, N. G.; Wassef, W. N.; Mohamed,
M. I. J. Prakt. Chem. 1989, 331, 405–410.
13. Doulut, S.; Dubuc, I.; Rodriguez, M.; Vecchini, F.;
Fulcrand, H.; Barelli, H.; Checler, F.; Bourdel, E.;
Aumelas, A.; Lallement, J. C.; Kitabgi, P.; Costentin, J.;
Martinez, J. J. Med. Chem. 1993, 36, 1369–1379.
14. Serra, S.; Fuganti, C. Synlett 2003, 2005–2008, and
relevant references reported therein.
Discover Focused Microwave Synthesis and subjected to
MW irradiation (power 300 W) for 5 min keeping tem-
perature below 120 ꢁC (air cooling). The crude reaction
mixture was evaporated and treated at reflux with HCl
8 N for 5 h. After cooling, the precipitate was collected
yielding a pale yellow solid proved to be a 1:2 mixture
(NMR determination) of the isomeric amino hydroxyl
naphthoic acids hydrochlorides 1a and 1b (70% starting
from 3).
15. Preparation
of
(E)-3-(methoxycarbonyl)-4-(3-nitro-
20. Compound 1a (hydrochloride): 1H NMR (300 MHz,
DMSO-d6), d 10.00 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H),
7.58 (d, J = 1.2 Hz, 1H), 6.98–6.82 (m, 3H), 6.00 (br s,
2H). Mp >250 ꢁC (dec). Anal. Calcd for C11H9NO3: C,
65.02; H, 4.46; N, 6.89. Found: C, 64.82; H, 4.45; N, 6.87.
phenyl)but-3-enoic acid (3). To a suspension of 2 (13.0 g,
35.2 mmol) in dry benzene (150 mL) 3-nitrobenzaldehyde
(5.74 g, 38.0 mmol) was added and the resulting mixture
was stirred at room temperature for 48 h and then
extracted with saturated NaHCO3 solution (3 · 70 mL).
The aqueous phase was washed with ethyl ether, acidified
with concentrated HCl and extracted with ethyl acetate
(3 · 60 mL). The combined organic phases were washed
with brine and dried. Evaporation of the solvent yielded
8.60 g (92%) of 3 as a white solid which was recrystallized
from toluene. Mp 160–161 ꢁC (lit. 122–123 ꢁC from
benzene, Ref. 12). Anal. Calcd for C12H11NO6: C, 54.34;
H, 4.18; N, 5.28. Found: C, 54.44; H, 4.19; N, 5.29. 1H
NMR (300 MHz, CDCl3) d 8.30–8.10 (m, 2H), 7.92 (s,
1H), 7.78–7.55 (m, 2H), 3.87 (s, 3H), 3.48 (s, 2H). MS (EI,
70 eV) m/z: 265. 1H NMR experiments confirmed the E
assignment for compound 3, as the chemical shift of the
vinylic hydrogen atom (d = 7.92 ppm) is consistent with a
cis position respect to the methoxycarbonyl substituent.
16. Preparation of (E)-3-(methoxycarbonyl)-4-(3-aminophen-
yl)but-3-enoic acid (4). To a solution of 3 (2.00 g,
7.54 mmol) in glacial acetic acid (100 mL) Zn dust
(3.88 g, 60.3 mmol) was added portionwise while keeping
the temperature below 20 ꢁC with an ice bath. The
resulting mixture was vigorously stirred for 24 h. The
solids were filtered off and washed with methanol and the
combined filtrates were concentrated and the residue was
redissolved in ethanol. The white precipitate formed was
filtered off and the solvent was evaporated. The TLC pure
crude residue was used immediately for subsequent
reaction. 1H NMR (300 MHz, CDCl3) 7.84 (s, 1H), d
7.22–7.12 (m, 1H), 6.78–6.65 (m, 3H), 5.73 (br s, 3H), 3.84
(s, 3H), 3.58 (s, 2H). MS (EI, 70 eV) m/z: 235.
1
MS (+ESI) m/z: 204; Compound 1b (hydrochloride): H
NMR (300 MHz, DMSO-d6), d 10.15 (br s, 1H), 7.90 (d,
J = 1.2 Hz, 1H), 7.57 (dd, J = 7.8 Hz, J = 7.8 Hz, 1H),
7.58–6.92 (m, 3H), 5.80 (br s, 2H). Mp >250 ꢁC (dec).
Anal. Calcd for C11H9NO3: C, 65.02; H, 4.46; N, 6.89.
Found: C, 64.92; H, 4.45; N, 6.88. MS (+ESI) m/z:
204.
21. Preparation of ethyl 7-amino-4-hydroxynaphthalene-2-car-
boxylate (5a) and ethyl 2,3-dihydro-2-oxonaphtho[1,8-de]-
[1,3]oxazine-8-carboxylate (6). Triethylamine (0.626 mL,
4.50 mmol) was added to a solution of esters 5a and 5b
(1.30 g, 5.62 mmol) in THF (100 mL) stirred at 0 ꢁC. A
solution of carbonyldiimidazole (0.730 g, 4.50 mmol) in
THF (30 mL) was then added dropwise and the mixture
was kept stirring at 0 ꢁC for 3 h. After quenching with
water, the mixture was evaporated and the resulting oil
was taken up with HCl 1 N (50 mL) and extracted with
chloroform (3 · 20 mL). The combined organic layers
were washed with HCl 1 N (2 · 10 mL) and with brine,
then dried and evaporated to furnish compound 6
(0.795 g, 55%) as a white solid: mp >250 ꢁC (dec); 1H
NMR (300 MHz, CDCl3) d 8.95 (br s, 1H), 8.25 (d,
J = 1.2 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.52 (d,
J = 8.4 Hz, 1H), 7.45 (dd, J = 8.4 and 7.2 Hz, 1H), 6.76
(d, J = 7.2 Hz, 1H), 4.44 (q, J = 7.3 Hz, 2H), 1.34 (t,
J = 7.3 Hz, 3H). Anal. Calcd for C14H11NO4: C, 65.37; H,
4.31; N, 5.44. Found: C, 65.24; H, 4.32; N, 5.43. MS (EI,
70 eV) m/z: 257. The combined aqueous phases were
basified with Na2CO3 and extracted with ethyl acetate
(3 · 30 mL). The combined organic layers were dried and
evaporated to recover unreacted compound 5a (0.430 g,
33%) which was used immediately for subsequent reaction.
1H NMR (300 MHz, CDCl3) d 8.03 (d, J = 8.0 Hz, 1H),
7.92 (d, J = 1.2 Hz, 1H), 7.18 (d, J = 1.2 Hz, 1H), 7.02–
6.96 (m, 2H), 5.50 (br s, 2H), 4.40 (q, J = 7.3 Hz, 2H), 1.41
(t, J = 7.3 Hz, 3H). MS (EI, 70 eV) m/z: 231.
17. Hayes, B. L. Microwave Synthesis: Chemistry at the Speed
of Light; CEM: Matthews, NC, 2002.
18. The reaction vessel was constantly irradiated at 300 W for
5 min total. The temperature was monitored using the
CEM Discover built-in vertically-focused IR temperature
sensor. Different reaction conditions such as conventional
heating or longer reaction time resulted in lower yields
(data not shown).
19. Preparation of 5-amino- and 7-amino-4-hydroxy-2-naph-
thoic acids (1a and 1b). A round-bottomed flask containing
a magnetic stirring bar and fitted with a reflux condenser
was charged with a mixture of 4, Ac2O (35 mL) and
NaOAc (1.5 equiv). The flask was placed in a CEM
22. Compound 5b: 1H NMR (300 MHz, CDCl3) d 8.02 (d,
J = 1.2 Hz, 1H), 7.46 (dd, J = 8.0 and 1.2 Hz, 1H), 7.37
(d, J = 1.2 Hz, 1H), 7.29 (dd, J = 8.0 and 7.8 Hz, 1H),
6.91 (dd, J = 7.8 and 1.2 Hz, 1H), 5.50 (br s, 2H), 4.38 (q,
J = 7.3 Hz, 2H), 1.39 (t, J = 7.3 Hz, 3H). MS (EI, 70 eV
m/z: 231.