Direct amination of naphthazarin, juglone, and some derivatives

Article abstract of DOI:10.1080/00397910701462864

Mono- and diamino-derivatives of naphthazarin, 2-methoxynaphthazarin, juglone and their methylethers were prepared by reaction with ammonia. The structure of the products was established by NMR studies. Some compounds were tested for cytotoxic activity. C

Full text of DOI:10.1080/00397910701462864

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Direct Amination of Naphthazarin, Juglone,
and Some Derivatives
Alberto Arnone a , Lucio Merlini b , Gianluca Nasini a & Orso Vajna de Pava a
a CNR‐ICRM, Department of Chemistry, Materials and Chemical Engineering,
Politecnico , Milano, Italy
b Department of Agri Food Molecular Sciences , University of Milano ,
Milano, Italy
Published online: 09 Aug 2007.
To cite this article: Alberto Arnone , Lucio Merlini , Gianluca Nasini & Orso Vajna de Pava (2007)
Direct Amination of Naphthazarin, Juglone, and Some Derivatives, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:15, 2569-2577, DOI:
10.1080/00397910701462864
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Synthetic Communicationsw, 37: 2569–2577, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701462864
Direct Amination of Naphthazarin, Juglone,
and Some Derivatives
Alberto Arnone
CNR-ICRM, Department of Chemistry, Materials and Chemical
Engineering, Politecnico, Milano, Italy
Lucio Merlini
Department of Agri Food Molecular Sciences, University of Milano,
Milano, Italy
Gianluca Nasini and Orso Vajna de Pava
CNR-ICRM, Department of Chemistry, Materials and Chemical
Engineering, Politecnico, Milano, Italy
Abstract: Mono- and diamino-derivatives of naphthazarin, 2-methoxynaphthazarin,
juglone and their methylethers were prepared by reaction with ammonia. The
structure of the products was established by NMR studies. Some compounds were
tested for cytotoxic activity.
Keywords: amination, naphthazarin, naphthoquinones
INTRODUCTION
Amino or imino derivatives of quinones have been the subject of recent
interest because of their occurrence as natural products and the variety of
their biological activity.[1] Methods of synthesis of these compounds are
known,[2] but only a few cases were reported of direct reaction of quinones
Received in Poland October 2, 2006
Address correspondence to Gianluca Nasini, CNR-ICRM, Department of
Chemistry, Materials and Chemical Engineering, Politecnico, via Mancinelli
720131, Milano, Italy. E-mail: gianluca.nasini@polimi.it
2569

2570
A. Arnone et al.
with ammonia.[3] The structural elucidation of the products is often made
difficult by the aminoquinone/iminoquinol tautomerism.[3a,4]
As a part of our studies of natural perylenequinones from fungi,[5] some
time ago we reacted cercosporin and phleichrome with ammonia in MeOH to
obtain mono- and diamino-derivatives.[6]
The amino-naphthoquinone moiety is a component of the molecular
framework of several natural products and has been used as a synthetic key
intermediate for the construction of several biologically important
compounds.[7] As a part of a program aimed at finding new cytotoxic
agents, we describe here the study on direct amination of naphthazarin
(NAPH), 2-methoxy-NAPH, juglone, and their methyl ethers and the
cytotoxic activity of some amino derivatives. It is interesting to note that
most recently the first natural polyhydroxylated naphthazarins with an
amino group, echinamines A and B, were isolated from a sea urchin,[8] and
their synthesis was reported,[9] but not via direct amination.
RESULTS AND DISCUSSION
Reaction of NAPH 1a with MeOH saturated with gaseous ammonia proceeded
slowly to give, after 24 h, in moderate yields, a mixture of mono (2, 3a) and
diamino (4) derivatives, which were separated by chromatography and ident-
ified on the basis of mass and NMR spectra (Scheme 1).
Compound 2 presented a mass of m/z 189, meaning that one of the
carbonyl or hydroxyl functions was substituted with an NH or NH2 group; its
1H NMR spectrum showed the presence of three exchangeable protons resona-
ting at 13.53 (OH-8), and 7.40 ppm (NH2-5) and two pairs of ortho-coupled
3
protons resonating at 6.97 and 6.98 ppm with J ¼ 10.2 Hz (H-2 and H-3)
Scheme 1.

Direct Amination of Naphthazarin
2571
and at 7.20 and 7.38 ppm with 3J ¼ 9.4 Hz (H-6 and H-7). These data are con-
sistent with structure 2 and with those reported in the literature.[10]
Compound 3a was analyzed for C10H7NO4. The presence in the 1H NMR
spectrum of two hydrogen bonded OH at 13.48 and 11.89 ppm, of a singlet at
5.96 ppm (H-2), and of the signals of an ortho system at 7.18 and 7.31 ppm
(3J ¼ 9.4 Hz) proved the formation of the mono-aminoderivative. Because
the sample was rather unstable, it was acetylated to give the diacetate 3b.
Again the structure of 3a was easily identified, because it had been already
synthesized from NAPH by amination with O-benzylhydroxylamine.[11]
Compound 4 exhibited a molecular peak in the mass spectrum at m/z 204,
suggesting the presence of an additional amino group with respect to 2.
1
Accordingly, the H NMR spectrum showed the presence of five protons
resonating at 15.55, 9.35, and 7.23 ppm (OH-8, NH2-5, and NH2-6), which
disappeared upon addition of D2O and three aromatic protons, two of them
(H-2 and H-3) ortho-coupled. The quaternary carbon at 105.32 ppm (C-8a)
presented in the 13C NMR spectrum three coupling constants (.1JCH) of
5 Hz with OH-8, H-2, and H-7, whereas the corresponding carbon at 106.68
.1
(C-4a) presented
carbonyl carbons at 175.05 and 181.15 ppm (C-1 and C-4) presented
J
of 5 Hz with H-3 and NH2-5. Moreover, the two
.1
CH
J
CH
of 10 Hz with H-3 and H-2 respectively. All these findings indicate the
structure 4 for the compound that derives from 2 or 3a by introduction of
an additional NH2 group. Treatment of 5,8-di-O-methylnaphthazarin (1b) in
the same conditions with gaseous ammonia in MeOH gave aminoquinone
3c as the main product.
A similar behavior is shown by 2-methoxy-NAPH (5), where the amino-
quinone 6 must undergo a phenol-quinone tautomerization, followed by
addition of ammonia onto carbon 4 (to give the imine 8) or 2 (to give the
aminoderivative 7) (Scheme 2).
Scheme 2.

2572
A. Arnone et al.
1
The H NMR spectrum of 7 reveals the presence of five exchangeable
protons (OH-5, NH2-2, and NH2-8), of one OMe group, and of two
aromatic singlets (H-3 and H-6). The fact that in a nuclear overhauser effect
(NOE) experiment, irradiation of OH-5 enhanced both H-3 and H-6
indicates that the first NH2 group must be linked at C-2. Moreover the
.1
presence of a
J
of 7 Hz between H-6 and the quaternary carbon at
CH
141.18 ppm allowed us to assign this carbon as C-8, its chemical shift indicat-
ing that it must be attached to the second amino group and not to an oxygen
atom. The structure of compound 6 follows from that of 7. The aromatic
1
pattern in its H NMR spectrum is similar to that of the starting compound
5, the only difference being the larger value of the ortho coupling constant
(10.3 vs. 9.5 Hz) and the upfield chemical shift of the corresponding
protons, due to the quinonoid nature of ring A. Because 6 gives 7, the
exchangeable protons must be assigned to OH-5 and NH2-8.
1
The H NMR spectrum of 8 exhibited the presence of one singlet at
6.22 ppm and of a pair of ortho-coupled protons resonating at different
chemical shift values, indicating that one of them is adjacent to the newly
entered amino group. Because the chelated hydroxy proton resonates at
higher field with respect to 6 (11.66 vs. 14.34), we tentatively assigned to
this compound the structure 8 in which the hydroxy proton is in peri
position with respect to an imino group and not to a quinonoid group.
In the case of juglone (9a) and its methylether (9b), a regioselective
addition of ammonia onto the quinone system occurs, with a different orientation
apparently induced by the OH and the OMe group respectively (Scheme 3).
The structures of 10 and 11 were established by comparison of their NMR
spectra with those reported by Parker and Sworin.[12] In all cases, a remarkable
regioselectivity of the addition of ammonia is again observed. In fact, this
regioselectivity can be explained by the electronic effects of the substituents
(Scheme 4).
It must be observed that all the compounds here reported are in a tauto-
meric equilibrium of the type shown in Scheme 5, the best example being
Scheme 3.

Direct Amination of Naphthazarin
2573
Scheme 4.
naphthazarin 1a, where the two forms are identical. In the other compounds,
the prevalent tautomeric form can be roughly estimated on the basis of the
chemical shift of the ring protons that have higher d values for the aromatic
with respect to the quinonoid form.[3] If we assume the value of 7.26 ppm
for naphthazarin 1a as representative of a 1:1 situation, we can suppose that
in compounds 2, 4, and 6, where the d values of the ortho-coupled H-2 and
H-3 protons are lower (6.98 and 6.97, 6.91 and 6.77, 6.94 and 6.92 respect-
ively) than for 1a, form B predominates, the opposite holding for
compounds 3a and 5 (7.18 and 7.31, 7.37 and 7.30 respectively).
A further comment is deserved about the trend of the chemical shift of the
hydrogen-bonded OH groups peri to the quinone carbonyls. There is a steady
increase of the chemical shift that is known to be related to the strength of the
intramolecular hydrogen bond, from 9a (11.80), to 1a (12.16), to 10 (13.37), to
2 (13.53), to 6 (14.34), to 7 (15.39), to 4 (15.55), clearly related to the increase
of the electron density on the carbonyl carbon, due to the introduction of
electron-donating groups in the rings.
Samples of compounds 4, 6, and 7 were tested for their cytotoxic activity
in vitro against the tumor cell line H460 and showed modest activity.

2574
A. Arnone et al.
Scheme 5.
In conclusion, we report a straightforward method of amination of
naphthoquinones that, even if the yields are in some cases modest, could be
applied successfully for the synthesis of such compounds.
EXPERIMENTAL
UV absorptions were measured for solutions in 95% EtOH. Mass spectra were
obtained with a Finnigan-MATT-TSQ 70-ev spectrometer; NMR spectra were
measured on a Bruker spectrometer operating at 400 MHz with Me4Si as
internal standard; HPLC analysis were performed using a LiChroCARTcol-
umn RP-18 (Merck) on an Agilent 1100 instrument. Flash-column chromato-
graphy was performed on Merck silica gel, thin-layer chromatography (TLC)
and preparative layer chromatography (PLC) with Merck HF254 silica gel. The
purity of products was checked by TLC, NMR, and MS and deemed sufficient
for the purpose of structural determination.
Compounds 1b[13] and 9b[14] were obtained by methylation of NAPH 1a
and juglone 9a respectively with MeI, Ag2O, and acetone dry at rt for 3 days in
the dark.
2-Methoxy-5,8-dihydroxy-[1,4]naphthoquinone (5)
NAPH (1a, 300 mg) was dissolved in 75 ml of CH3CN; the solution was saturated
with Cl2 and exposed to daylight in a Pyrexw container for 15 min. The solvent
was evaporated, and a saturated solution of MeONa in MeOH (200 mg of Na
in 55 ml MeOH) was added; the mixture was refluxed for 3 days. The residue
was chromatographed on silica gel containing 4% of K2HPO4 with CH2Cl2
(30:1) as eluent to yield 80 mg of 5: red crystals, mp 190–1958C, m/z 220
1
(Mþ); H NMR (CDCl3): d 12.66 and 12.19 (2H, s, OH-5 and -8), 7.30 and
7.22 (2H, d, J ¼ 9.5 Hz, H-6 and -7), 6.18 (1H, s, H-3), 3.95 (3H, s, OMe).
General Procedure for Amination
To 100 mg each of compounds 1a, 1b, 5, 9a, and 9b dissolved in MeOH
(20 ml), a saturated solution of NH3 in MeOH (5 ml) was added; after 24 h

Direct Amination of Naphthazarin
2575
the solvent was evaporated, and the residue was chromatographed on a column
of silica gel (with added 4% KH2PO4) with CH2Cl2-MeOH as eluent
(gradient) and purified further by preparative TLC using a mixture of
CH2Cl2-MeOH-HCOOH (15:1:0.5 v/v) as eluant to give compounds 2, 3a,
3c, 4, 6, 7, 8, 10, and 11 respectively.
Data
5-Amino-8-hydroxy-[1,4]naphthoquinone (2). Yield 10%, mp 245–2508C
dec., H NMR (250.1 MHz, acetone-d6): d 13.53 (br s, 1H, OH-8), 7.40 (br
1
signal, 2H, NH2-5), 7.38 and 7.20 (d, J ¼ 9.4 Hz, 2H, H-7 and -6), 6.98 and
6.97 (d, J ¼ 10.2 Hz, 2H, H-2 and -3).
3-Amino-5,8-dihydroxy-[1,4]naphthoquinone (3a). Yield 13%, mp
1
.2708C dec., H NMR (acetone-d6): d 13.48 (s, 1H, OH-8), 11.89 (s, 1H,
OH-5), 7.31 and 7.18 (d, J ¼ 9.4 Hz, H-7 and -6), 6.85 (br signal, 2H, NH2-
3), 5.96 (s, 1H, H-2), m/z 205(Mþ). Found: C, 58.83; H, 3.25; N, 6.67;
C10H7NO4 requires C, 58.54; H, 3.44; N, 6.83.
3-Amino-5,8-diacetoxy-[1,4]naphthoquinone (3b). 1H NMR (CDCl3): d
7.36 and 7.27 (d, J ¼ 9.8 Hz, 2H, H-7 and -6), 5.84 (s, 1H, H-2), 5.03 (br
signal, 2H, NH2-3), 2.43 and 2.42 (s, 6H, 2xOAc).
3-Amino-5,8-dimethoxy-[1,4]naphthoquinone (3c). Yield 68%, mp 216–
1
2208C, m/z 233 (Mþ); H NMR (CDCl3): d 7.34 and 7.23 (d, J ¼ 9.8 Hz,
2H, H-7 and -6), 5.88 (s, 1H, H-2), 4.98 (br signal, 2H, NH2-3), 3.96 and
3.93 (s, 6H, 2xOMe).
5,6-Diamino-8-hydroxy-[1,4]naphthoquinone (4). Yield 30%, mp 191–
1
1958C, H NMR (DMSO-d6): d 15.55 (s, 1H, OH-8), 9.35 (br signal, 2H,
NH2-5), 7.23 (br s, 2H, NH2-6), 6.91 and 6.77 (d, J ¼ 9.8 Hz, H-2 and -3),
6.05 (s, 1H, H-7). 13C NMR (62.9 MHz, DMSO-d6): d 181.15 (C-4); 175.05
(C-1); 168.37 (C-8); 149.97 (C-6); 142.02 (C-5); 137.75 (C-3); 135.86
(C-2); 106.68 (C-4a); 105.32 (C-8a); 101.05 (C-7).
5-Hydroxy-7-methoxy-8-amino-[1,4]naphthoquinone (6). Yield 15%, mp
1
218–2228C, m/z 219 (Mþ); H NMR (CDCl3): d 14.34 (s, 1H, OH-5), 9.20
(br signal, 2H, NH2 -8), 6.94 and 6.92 (d, J ¼ 10.3 Hz, 2H, H-2 and -3),
6.50 (s, 1H, H-6), 4.00 (s, 3H, OMe-7).
2,8-Diamino-5-hydroxy-7-methoxy-[1,4]naphthoquinone (7). Yield 25%,
1
mp 214–2208C, m/z 234 (Mþ); H NMR (DMSO-d6): d 15.39 (s, 1H, OH-
5), 9.11 (br signals, 2H, NH2-8), 7.25 (br signals, 2H, NH2-2), 6.62 (s, 1H,
1
H-6), 5.72 (s,1H, H-3), 3.92 (s, 3H, OMe-7). H NMR (NOEs, DMSO-d6):

2576
A. Arnone et al.
irradiation of H-6 enhanced OH-5 (2%) and OMe-7 (4%); irradiation of OH-5
enhanced H-3 (1.5%) and H-6 (2%); irradiation of OMe-7 enhanced H-6
(8.5%). 13C NMR (DMSO-d6): d 184.20 (C-4); 178.04 (C-1); 157.88 (C-5);
153.59 (C-7); 152.56 (C-2); 141.18 (C-8); 106.02 (C-6); 105.79 (C-8a);
103.71 (C-4a); 100.24 (C-3); 56.44 (OMe). HREIMS, m/z 234.0654
(C11H10N2O4 requires 234.0640).
8-Amino-5-hydroxy-4-imino-7-methoxy-4H-naphthalene-1-one
(8).
Compound 8 was obtained by treating 6 with NH3 37% at 508C for 30 min.
1
Yield 55%. M/z 218 (Mþ), H NMR (acetone-d6): d 11.66 and 7.48 (br
signals, 4H, NH2, NH and OH), 7.24 and 6.77 (d, J ¼ 9.8 Hz, 2H, H-2 and
-3), 6.22 (s, 1H, H-6), 3.97 (s, 3H, OMe-7). HREIMS, m/z 218.0663
(C11H10N2O3 requires 218.0691).
3-Amino-8-hydroxy-[1,4]naphtoquinone (10). Yield 20%, mp 180–1868C, m/z
1
189 (Mþ); H NMR (DMSO-d6): d 13.37 (s, 1H, OH-8), 7.90 and 7.52 (br
signals, 2H, NH2-3), 7.56 (dd, J ¼ 8.5 and 8.2 Hz, 1H, H-6), 7.48
(br,J ¼ 8.2 Hz, 1H, H-5), 7.27 (br, J ¼ 8.5 Hz, 1H, H-7). 13C NMR
(DMSO-d6): d 188.79 (C-1); 181.65 (C-4); 160.54 (C-8); 152.31 (C-3); 134.53
(C-6); 130.99 (C-4a); 125.41 (C-7); 118.75 (C-5); 114.95 (C-8a); 101.03 (C-2).
2-Amino-8-methoxy-[1,4]naphtoquinone (11). Yield 60%, mp 154–1588C,
m/z 203 (Mþ); 1H NMR (CDCl3): d 7.75 (br d, J ¼ 8.2 Hz, 1H, H-5), 7.67 (dd,
J ¼ 8.4 and 8.2 Hz, 1H, H-6), 7.21 (br d, J ¼ 8.4 Hz, 1H, H-7), 5.94 (s, 1H,
H-3), 5.29 (br signal, 2H, NH2-2), 4.02 (s, 3H, OMe-8).
Cytotoxicity Assay
Some compounds were tested for their cytotoxicity against the non-small cell
lung tumor cell line H460 and showed modest activity [IC50 (mM): 16.5 for 4,
26.5 for 6 and 72.0 for 7].
ACKNOWLEDGMENTS
We thank G. Pratesi (Istituto Nazionale dei Tumori, Milano) for the cytoto-
xicity tests and Italian Ministry of University and Research (MIUR) (funds
for basic research [FIRB] Project 2003) for financial support.
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