New synthetic routes for the preparationof 2-Amino-3-hydroxy-1,4- naphthoquinone

Full text of DOI:10.1080/00304940903078251

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Organic Preparations and Procedures
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New Synthetic Routes for the
Preparation of 2-Amino-3-hydroxy-1,4-
naphthoquinone
Acácio I. Francisco a , Annelise Casellato a & Maria D. Vargas a
a Instituto de Química, Universidade Federal Fluminense , Campus
do Valonguinho , Niterói, RJ, 24020-141, Brazil
Published online: 10 Jul 2009.
To cite this article: Acácio I. Francisco , Annelise Casellato & Maria D. Vargas (2009) New Synthetic
Routes for the Preparation of 2-Amino-3-hydroxy-1,4-naphthoquinone, Organic Preparations
and Procedures International: The New Journal for Organic Synthesis, 41:4, 323-326, DOI:
10.1080/00304940903078251
To link to this article: http://dx.doi.org/10.1080/00304940903078251
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Organic Preparations and Procedures International, 41:323–326, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903078251
OPPI BRIEFS
New Synthetic Routes for the Preparation
of 2-Amino-3-hydroxy-1,4-naphthoquinone
Aca´cio I. Francisco, Annelise Casellato, and Maria D. Vargas
Instituto de Qu´ımica, Universidade Federal Fluminense, Campus do
Valonguinho Nitero´i, RJ, 24020-141, Brazil
On the basis of biological and structural properties, 1,2- and 1,4-naphthoquinones are
considered privileged structures in medicinal chemistry.1 The presence of a nitrogen atom
in quinone compounds is also related with a wide range of biological properties, such as
anticancer2 and antimalarial3 activities. In addition, the amino naphthoquinone moiety is
a component of the molecular framework of several natural products (e. g. rifamycins,
kinamycins, etc.).4,5
2-Amino-3-hydroxy-1,4-naphthoquinone (2) has been prepared by: i) catalytic hy-
drogenation of 2-hydroxy-3-nitro-1,4-naphthoquinone6,7 in the presence of PtO2,8 or
ii) reduction of 2-hydroxy-3-nitroso-1,4-naphthoquinone with Na2S2O4 or NaBH4,9 re-
sulting in low yields of quinone 2 (53% and 45%, respectively). We now report two new
synthetic routes to 2-amino-3-hydroxy-1,4-naphthoquinone (2) in yields better than previ-
ously reported in the literature.8,9
Both routes start from 3-(4ꢀ-nitrophenylazo)-4-hydroxy-1,2-naphthoquinone (1) which
was prepared from the coupling reaction of the diazonium salt of 4-nitroaniline with 2-
hydroxy-1,4-naphthoquinone in basic medium, as described in the literature.10 The product
precipitates immediately and is obtained in a pure form in 92% yield. It is poorly soluble in
usual organic solvents. This reaction is very clean and generates no by-products. The first
route involves the reaction compound 1 in the presence of Raney nickel and formic acid,
in MeOH, at room temperature. Protonation of the azo group of 1, followed by cleavage of
the N = N bond gives 2 and 4-nitroaniline. After extraction with CHCl3 and washing with
water we were able to recover part of the 4-nitroaniline used in the preparation of 1 and
obtain the desired product 2 in good yield (82%). This methodology has been reported to
selectively reduce aromatic nitro compounds.11 The second route involves the reduction of
Submitted October 9, 2008.
Address correspondence to Aca´cio I. Francisco, Instituto de Qu´ımica, Universidade Federal Flu-
minense, Campus do Valonguinho, Nitero´i, RJ, 24020-141, Brazil. E-mail: acacioivo@yahoo.com.br
323

324
Francisco, Casellato, and Vargas
1 with Sn/HCl under reflux12 which gives product 2 in 78% yield and 4-nitroaniline after
the same work out procedure.
Scheme 1
Route 1. i) Raney Ni, MeOH, 1h.; ii) HCOOH at RT. Route 2. i) Sn/conc.HCl, EtOH, reflux,
2h; ii) NaOH.
The overall yields of product 2 from both routes are quite good (78%–82%), when
compared to those described previously (53%–45%).8,9 Furthermore another disadvantage
of the catalytic hydrogenation of compound 2-hydroxy-3-nitro-1,4-naphthoquinone,8 when
compared to routes 1 and 2 described in this paper, is the use of expensive PtO2.
Interestingly, reduction of 3-(phenylazo)-4-hydroxy-1,2-naphthoquinone13 (mp
253–255◦C, lit.13 253–254◦C), which has been synthesized as described for 1 from 2-
hydroxy-1,4-naphthoquinone and the diazonium salt of aniline, under the conditions of the
two routes does not result in the formation of the desired product 2.
Experimental Section
Mps were determined in capillary tubes on a Mel-Temp II, Laboratory Devices, USA and
are uncorrected. The NMR spectra were recorded on a Varian 300 MHz spectrometer.
Chemical shifts are reported in δ relative to TMS as internal reference. The IR spectrum
was recorded on a FT-IR Spectrum One (Perkin-Elmer) (KBr). The UV-vis spectrum was
obtained with a Diode Array 8452A (Hewlett Packard–HP) spectrometer, in spectroscopic
grade chloroform and dimethyl sulfoxide.
Preparation of Compound 1
A mixture of 0.915 g (6.63 mmol) of 4-nitroaniline, 3.5 mL of water and 3.5 mL of conc.
HCl was stirred until dissolution. The solution was then cooled by the addition of crushed ice
(1.00 g) to the solution. When the solution temperature reached 0◦C, 0.303 g (4.39 mmol)
Table 1
Yields (%) of 2 from the two Synthetic Routes Described
Product
Overall Yield from
Route
2 from 1
2-hydroxy-1,4-naphthoquinone
1
2
89
85
82
78

Preparation of 2-Amino-3-hydroxy-1,4-Naphthoquinone
325
Table 2
1H NMR data (CDCl3, 300 MHz) of 2-Amino-3-hydroxy-1,4-naphthoquinone
H5
H6
H7
H8
δ 7.97; 1H, dd
J = 6.89
δ 7.61; 1H, dt
J = 6.89, 6.89
and 2.40 Hz
δ 7.71; 1H, dt
J = 6.89, 6.89
and 3.28 Hz
δ 8.04; 1H, dd
J = 6.89
and 3.28 Hz
and 2.40 Hz
of NaNO2 in 2 mL of cold water was added to the mixture. The solution was stirred at 0◦C
for 20 min., then added dropwise to a stirred solution of 2-hydroxy-1,4-naphthoquinone
(0.635 g, 3.65 mmol) and sodium hydroxide (0.438 g, 10.95 mmol) in ethanol (28 mL)
kept at 0◦C. The resulting orange solid, mp 275–276◦C, lit.10 273–274◦C, was collected
and washed with cold water and ethanol and dried under vacuum (1.08 g, 92%).
Preparation of 2-Amino-3-hydroxy-1,4-naphthoquinone (2)
Route 1. To a stirred suspension of 1.00 g (3.10 mmol) of 1 and 0.15 g of Raney nickel in
10 mL of MeOH at room temperature was added formic acid (90%) (4 mL). The reaction
monitored by TLC (ethyl acetate/hexane 3:7) was completed in 1 h. The mixture was filtered
through Celite to remove all the Raney nickel. The filtrate was extracted with CHCl3 (3 ×
30 mL). Following addition of a 2M solution of NaOH (12 mL) to the aqueous phase to
adjust the pH to 9, 4-nitroaniline precipitated. The organic layer was dried over MgSO4,
and evaporation of the solvent gave 0.497 g (2.63 mmol, 86%) of 2-Amino-3-hydroxy-1,4-
naphthoquinone (2) as a purple solid,6 mp. 131–132◦C, lit.8 130–149◦C.
Route 2. To a stirred mixture of 1 (1.00 g, 3.10 mmol) in 13 mL of conc. hydrochloric
acid and 20 mL of ethanol was added granulated tin (2.225 g, 20 mmol) and the reaction
mixture was heated under reflux for 4 h. After the mixture had cooled, addition of water
(100 mL) was followed by addition of solid NaOH (0.219 g, 5.47 mmol) to adjust the
pH to 14. The tin oxide was filtered off through filter paper and the dark orange filtrate
Table 3
13C NMR Data (CDCl3, 75 MHz) of 2-Amino-3-hydroxy-1,4-naphthoquinone
C1
C2
C3
C4
C4a
C5
C6
C7
C8
C8a
177.7 135.9 133.2 181.9 130.3 125.1 132.5 133.8 124.9 130.1

326
Francisco, Casellato, and Vargas
(approximately 30 mL) was transferred to a separation funnel together with the same
volume of dichloromethane; slow addition of 6M HCl led to extraction of the product to the
organic phase. The extraction procedure was repeated twice again. The bright red extracts
were combined and dried over MgSO4. Evaporation of the solvent gave 0.497 g (86%) of
2-amino-3-hydroxy-1,4-naphthoquinone as a purple solid.8
Acknowledgements
The authors thank the Brazilian agencies CNPq, FAPERJ, Capes and Pronex-FAPERJ for
financial support.
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