Complex diazaazulenones from the reaction of ortho -naphthoquinones with ammonium acetate

Article abstract of DOI:10.1055/s-0030-1258502

Complex diazaazulenones compounds were obtained from ortho-naphthoquinones by reaction with ammonium acetate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258502

LETTER
1931
Complex Diazaazulenones from the Reaction of ortho-Naphthoquinones with
Ammonium Acetate
C
omplexDiaz
l
aazule
n
a
ones vio S. Emery,a,d Maria do Carmo F. R. Pinto,a Carlos A. de Simone,b,c Valéria R. S. Malta,b
Eufrânio N. da Silva Júnior,*a Antonio V. Pintoa
a
Núcleo de Pesquisas de Produtos Naturais, UFRJ, 21944-971, Rio de Janeiro, RJ, Brazil
Fax +55(21)25626512; E-mail: eufranio.junior@yahoo.com.br
Instituto de Química e Biotecnologia, UFAL, 57072-970, Tabuleiro do Martins, Maceió, Al, Brazil
Departamento de Física e Informática, Instituto de Física, USP, 13560-160, São Carlos, SP, Brazil
b
c
d
Faculdade de Ciências Farmacêuticas, USP, 14040-903, Ribeirão Preto, SP, Brazil
Received 31 March 2010
This paper is dedicated in the memory of our beloved Professor Antonio Ventura Pinto, who passed away on March 18th, 2010.
er severe diseases7 and emerge as important chemothera-
Abstract: Complex diazaazulenones compounds were obtained
peutic prototypes.
from ortho-naphthoquinones by reaction with ammonium acetate.
In one of our publications employing quinoidal com-
Key words: lapachones, heterocycles, diazaazulenone, X-ray crys-
pounds, it was reported that the reaction of b-lapachone
(2) and nor-b-lapachone (3) with ammonium acetate
yielded complex reaction mixtures of products in both
cases.5b
tallography
Heterocycles are an important class of compounds with
diverse medicinal applications.1–3 Lately, new heterocy-
cles obtained from naphthoquinoidal compounds were de-
veloped,4 starting from naturally occurring quinoidal
compounds, such as lapachol (1) and b-lapachone (2), re-
sulting in macrolactones, oxazoles, and other important
compounds5 (Scheme 1). In addition, some of these het-
erocyclic compounds showed activity against cancer cell
lines,6 the etiological agents of Chagas’ disease,2 malaria
(Plasmodium falciparum)3 and also against agents of oth-
In a preliminary study, it was possible to identify fluores-
cent symmetric phenazines 4 and 5 from nor-b-lapachone
(3), and compounds 6 and 7 from b-lapachone (2), respec-
tively. The phenazines in each reaction were present in the
more apolar fractions eluted from chromatographic col-
umns (Scheme 2).5b These phenazinic compounds present
very important photophysical properties.8a However, the
more polar products from these reactions have not been
studied until now. What follows is the first report of the
O
N
O
N
+
O
O
N+
N
O–
O
O
O
O
O
O
O
N
N
O
O
O
ref. 5c
ref. 5d
ref. 5a
O
O
O
N
O
OH
ref. 5b
N
O
N
ref. 4a
O
1
Scheme 1 Heterocycles obtained from lapachol (1) via several reactions types
SYNLETT 2010, No. 13, pp 1931–1934
x
x
.x
x
.2
0
1
0
Advanced online publication: 16.07.2010
DOI: 10.1055/s-0030-1258502; Art ID: S01710ST
© Georg Thieme Verlag Stuttgart · New York

1932
F. S. Emery et al.
LETTER
O
O
n
O
N
N
N
N
AcOH, AcONH4
+
or pyridine, glycine
O
O
n
O
O
n
n
n
5, n = 1
7, n = 2
3, n = 1
2, n = 2
4, n = 1
6, n = 2
Scheme 2 Fluorescent symmetric phenazines from b-lapachone (2) and nor-b-lapachone (3)
structure of more the polar products from these two reac-
tions.
The reactions of b-lapachone (2) and nor-b-lapachone (3)
with ammonium acetate were carried out in acetic acid so-
lution at reflux temperature. After vacuum evaporation of
the solvent, the crude extract was eluted in a silica gel
chromatographic column with a gradual increase of sol-
vent polarity. In both reactions a bright yellow phenazinic
fluorescent product was isolated.
In proceeding with elution, at the corresponding polarity
of 2.5–3.5% (EtOAc–hexane) of the solvent system, com-
pounds 8 and 9 were obtained from 3. From the reaction
of 2, only 10 was isolated in the polarity corresponding to
3.5% of ethyl acetate in hexane (Scheme 3).
Figure 1 An ORTEP-3 projection, showing the atomic labelling
and the 50% probability ellipsoids of compound 9
Only one diazaazulenic isomer was obtained from com-
pound 2, the transoid isomer. As a hypothesis, we suggest
that the larger pyran cycles in the intermediate favors this
diasteromer in relation to the cisoid one, with two pyran
groups on the same side.
Notably, the MS of 8 and 9 showed the same fragmenta-
tion pattern and similar m/e values for the molecular ions
(m/e = 436) indicating an isomeric relationship between
these two structures. The MS of 10 suggests that this com-
pound is the next superior homologue of 9 (m/e = 464).
The proposed structures of all compounds are in agree-
ment with their respective spectral data, such as 1H NMR,
13C NMR, IR, UV/vis, and MS data. Compound 9, the
transoid isomer, was reconfirmed by X-ray crystallogra-
phy (Figure 1).9–11
The structural correlation between 8, 9, and 10 are corro-
borated by IR spectra and these compounds have almost
the same absorption band for the carbonyl groups, at
1665, 1663, and 1667 cm–1, respectively.
2
3
1
6
O
O
O
O
O
O17
7
8
5
O
OH
4
AcONH4, AcOH
reflux, 1.5 h
H2SO4
16
N
N
15
9 O
13
1
2
14
10
12
10 (10%)
11
3 steps
H'
2
H'
2
H
H
H'
3
3
6
6
1
O
H O
O
O
O 1
7
8
5
5
4
O
4
7 O
AcONH4, AcOH
reflux, 1.5 h
15
14
N
15
N
N
+
14
N
8
9
12
12
O
13
O
13
11
11
H'
9
10
10
H
3
9 (11%)
8 (11%)
Scheme 3 Diazaazulenones obtained from b-lapachone (2) and nor-b-lapachone (3)
Synlett 2010, No. 13, 1931–1934 © Thieme Stuttgart · New York

LETTER
Complex Diazaazulenones
1933
The 13C NMR spectra of 8, 9, and 10 showed similar the diazaazulenone structures. Intermediate 12 can ex-
chemical shifts for the carbonyls, at d = 160.8, 161.3, and plain the formation of cisoid and transoid derivatives for
162.2 ppm, respectively, being compatible with carbonyl nor-b-lapachone (3).
lactams from what would be expected for the proposed di-
In conclusion, we have described a new chemical reaction
azaazulenone compounds. In the 1H NMR spectra for the
path of quinoidal compounds for the formation of diazaa-
transoid diazaazulenone 9 it was observed that the meth-
ylenic hydrogens H3 and H3¢ at d = 3.4 or 3.6 ppm and
H11 and H11¢ at d = 3.4 or 3.6 ppm have similar chemical
shifts. In comparison with the one cisoid isomer, com-
pound 8, the methylenic hydrogens H3 and H3¢ at d = 3.3
or 3.8 ppm and H5 and H5¢ at d = 3.3 or 3.8 ppm, indicat-
ing that the carbonyl group deshields the latter methylenic
hydrogens in the furanic ring, supporting the interpreta-
tion of a cisoid structure.
zulenone structures.12 The easy preparation of the com-
plex heterocycles in one step using simple substrates and
reagents clearly demonstrates the importance of this line
of attack.
Acknowledgment
This work was supported by CNPq (National Council of Research
of Brazil), CAPES, FAPERJ, UFAL, USP and UFRJ. Dr. Eufrânio
N. da Silva Júnior thanks the CNPq for post doctoral financial sup-
port (project no. 151558/2009-4). The authors are also indebted to
the PRONEX-FAPERJ (E-26/171.512.2006).
In compound 10, the furanic methylenes showed very
similar shifts in the NMR spectra, at d = 3.1 and 3.3 ppm
for H2, H3, H11, and H10, respectively. The signals of the
furanic methylenes and the aromatic hydrogen being quite
comparable to the ones of 9 suggests that 10 is also a tran-
soid diazaazulene.
References and Notes
(1) Calas, M.; Ouattara, M.; Piquet, G.; Ziora, Z.; Bordat, Y.;
Ancelin, M. L.; Escale, R.; Vial, H. J. Med. Chem. 2007, 50,
6307.
For the formation of these compounds the mechanism
proposed is shown in Scheme 4.8b The formation of diaz-
aazulenones from naphthoquinones 3 must go on from the
initial formation of intermediate 11 that then rearranges to
(2) Kuettel, S.; Zambon, A.; Kaiser, M.; Brun, R.; Scapozza, L.;
Perozzo, R. J. Med. Chem. 2007, 50, 5833.
(3) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J.
Org. Chem. 2006, 51.
O
O
(4) (a) Emery, F. S.; Silva, R. S. F.; de Moura, K. C. G.; Pinto,
M. C. F. R.; Amorim, M. B.; Malta, V. R. S.; Santos, R. H.
A.; Honório, K. M.; da Silva, A. B. F.; Pinto, A. V. An. Acad.
Bras. Cienc. 2007, 79, 29. (b) da Silva Júnior, E. N.; Souza,
M. C. B. V.; Pinto, A. V.; Pinto, M. C. F. R.; Ferreira, V. F.;
Menna-Barreto, R. F. S.; Silva, R. S. F.; Teixeira, D. V.;
de Simone, C. A.; de Castro, S. L. Eur J. Med. Chem. 2008,
1774. (c) da Silva, F. C.; Jorqueira, A.; Gouvêa, R. M.;
de Souza, M. C. B. V.; Howie, R. A.; Wardell, J. L.;
Wardell, S. M. S. V.; Ferreira, V. F. Synlett 2007, 3123.
(5) (a) Andrade-Neto, V. F.; Goulart, M. O. F.; Silva Filho, J. F.;
da Silva, M. J.; Pinto, A. V.; Pinto, M. C. F. R.; Zalis, M. G.;
Carvalho, L. H.; Krettli, A. U. Bioorg. Med. Chem. Lett.
2004, 14, 1145. (b) Pinto, A. V.; Pinto, C. N.; Pinto, M. C.
F. R.; Emery, F. S.; de Moura, K. C. G.; Carvalho, C. E. M.;
Brinn, I. M. Heterocycles 1998, 45, 2491. (c) Yang, R. Y.;
Kizer, D.; Wu, H.; Volckova, E.; Miao, X. S.; Ali, S. M.;
Tandon, M.; Savage, R. E.; Chan, T. C. K.; Ashwell, M. A.
Bioorg. Med. Chem. 2008, 16, 5635. (d) da Silva Júnior,
E. N.; de Simone, C. A.; de Souza, A. C. B.; Pinto, C. N.;
Guimarães, T. T.; Pinto, M. C. F. R.; Pinto, A. V.
Tetrahedron Lett. 2009, 50, 1550.
O
3
AcONH4, AcOH
O
O
N
H
N+
N
NH
CO2H
O
OH2
O
O
11
12
(6) da Silva Júnior, E. N.; de Moura, M. A. B. F.; Pinto, A. V.;
Pinto, M. C. F. R.; de Souza, M. C. B. V.; Araújo, A. J.;
Pessoa, C.; Costa-Lotufo, L. V.; Montenegro, R. C.;
de Moraes, M. O.; Ferreira, V. F.; Goulart, M. O. F. J. Braz.
Chem. Soc. 2009, 20, 635.
O
O
(7) Nicolaides, D. N.; Gautam, D. R.; Litinas, K. E.;
Hadjipavlou-Litina, D. J.; Fylaktakidou, K. C. Eur. J. Med.
Chem. 2004, 323.
O
O
+
N
N
N
N
(8) (a) Carvalho, C. E. M.; Lucas, N. C.; Herrera, J. O. M.; Pinto,
A. V.; Pinto, M. C. F. R.; Brinn, I. M. J. Photochem.
Photobiol. A: Chem. 2004, 167, 1. (b) Lantos, I. J. Org.
Chem. 1975, 40, 1641.
O
O
(9) A orange crystal (0.086 × 0.150 × 0.240) mm3 of compound
9 was selected for X-ray diffraction. Intensity data were
collected at r.t. (T = 298K) using a diffractometer Kappa
CCD of Enraf Nonius with MoKa monochromatic radiation
8
9
Scheme 4 Mechanism proposed for the formation of diazaazulen-
one compounds from lapachones
Synlett 2010, No. 13, 1931–1934 © Thieme Stuttgart · New York

1934
F. S. Emery et al.
LETTER
(l = 0.71073 Å) and using the Collect10a software, as well as
Scalepack10b for cell refinement. The compound 9 was
measured a total of 4349 reflections to a maximum 2q of
27.42°. No significant absorption effect (m = 0.088 mm–1)
for compound 9 was revealed, so no absorption correction
was applied. The crystal structure for compound 9 was
solved by direct methods and refined anisotropically with
full matrix least square on F2 using SHELXL-97 program.10c
H atoms attached to C atoms were located on stereochemical
grounds placed (C–H = 0.93–0.98 Å) and refined as riding
with Uiso(H) = 1.5 Ueq (C-methyl) or 1.2 Ueq(other) times the
value of the equivalent isotropic displacement parameter of
atoms to which they are bonded. The software used were:
data collection: COLLECT;10a cell refinement: HKL
SCALEPACK;10b data reduction: HKL DENZO and
SCALEPACK.10b The program (s)used to solve structure:
SHELXS-97.10d The program (s)used to refine structure:
SHELXL-97.10c molecular graphics: ORTEP-3, software
used to prepare material for publication: WinGX.10e
Crystallographic data for compounds 9 have been deposited
with the Cambridge Crystallographic Data Center as
Supplementary Publication No. CCDC 739857. Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CH21EZ, UK (fax:+44
1223 336 033 or e-mail: deposit@ccdc.cam.ac.uk).
in percentage of the base peak intensity. Lapachol(1) was
extracted from the hardwood Tabebuia sp. (Tecoma) and
purified by a series of recrystallizations with the appropriate
solvent.13a b-lapachone (2) was obtained by acid cyclization
from lapachol (1) by Hooker’s methodology.13b
General Procedure for the Synthesis of the Compounds
8–10
To 1.0 mmol of b-lapachone (2) or nor-b-lapachone (3) in a
solution of glacial AcOH (10.0 mL), was added NH4OAc
(14.4 mmol), followed by reflux for 2.5 h. After cooling, the
reaction medium was poured in H2O, and the solid residue
was filtered under vacuum, washed with water for
neutralization and soon after the solid was chromatographed
in a silica gel column starting with hexane as eluent. In
preparing 8, the compound was found in a polarity
corresponding to 2.5% of the EtOAc–hexane gradient. In
obtention of 9, the compound was chromatographed in the
EtOAc–hexane gradient corresponding to 3.5%. Compound
10 was obtained in the EtOAc–hexane gradient
corresponding to 3.5%. The orange solids were
recrystallized in a mixture of hexane–acetone (1:1).
Spectroscopic Data of Compound 8
Orange crystals; mp 244–245 °C; yield 11.2%. IR (KBr):
3064, 2963, 2924, 2851, 1665, 1629, 1499, 1388, 1284,
1172, 1074, 1062, 1020, 870, 759, 703 cm–1. 1H NMR (200
MHz, CDCl3): d = 9.4 (dd, 1 H), 8.8 (dd, 1 H), 8.1 (dd, 2 H),
7.6 (m, 4 H), 3.8 (s, 2 H), 3.3 (s, 2 H), 1.6 (s, 12 H). 13C NMR
(50 MHz, CDCl3): d = 160.8, 159.5, 153.6, 144.2, 133.5,
131.3, 129.0, 127.2, 126.4, 125.7, 125.3, 123.2, 122.7,
122.2, 120.1, 108.4, 107.4, 86.2, 85.7, 47.7, 45.1, 29.6, 28.4,
28.2. UV (EtOH): lmax (log e) = 373.0 (4.09), 328.5 (4.29),
315.5 (4.27), 264.5 (4.36), 228.0 (4.49), 205.5 (4.40) nm.
MS (70 eV): m/z (%) = 437 (33), 436 (100), 421 (15), 393
(8,0), 341 (8,0), 325 (20), 297 (6), 218 (5).
(10) (a) Enraf-Nonius (1997–2000). COLLECT. Nonius B. V.,
Delft, The Netherlands. (b) Otwinowski, Z.; Minor, W.
Methods Enzymol. 1997, 276, 307. (c) Sheldrick, G. M.
SHELXL-97: Program for Crystal Structures Analysis;
University of Göttingen: Göttingen / Germany, 1997.
(d) Sheldrick, G. M. SHELXS-97: Program for Crystal
Structure Resolution; University of Göttingen: Göttingen /
Germany, 1997. (e) Farrugia, L. J. J. Appl. Cryst. 1997, 30,
565.
(11) Crystal Data and Structure Refinement for Compound 9
Empirical formula: C28H24N2O3; formula weight: 436.49;
temperature: 295 (2) K; wavelength: 0.71073 Å; crystal
system: monoclinic; space group: Pn; unit cell dimensions:
a = 5.32360 (10) Å, b = 9.9426 (3) Å, b = 95.6930 (10)°,
c = 20.1385 (7) Å; volume: 1060.68 (5) Å3; Z: 2;
Spectroscopic Data of Compound 9
Orange crystals; mp 265–268 °C; yield 11.2 (%). IR (KBr):
3074, 3058, 2976, 2928, 2856, 1663, 1630, 1601, 1531,
1460, 1385, 1276, 1250, 1117, 1069, 867, 752, 710 cm–1. 1H
NMR (200 MHz, CDCl3): d = 9.3 (dd, 1 H), 8.4 (dd, 1 H),
8.1 (m, 2 H), 7.6 (m, 4 H), 3.6 (s, 2 H), 3.4 (s, 2 H), 1.6 (s,
12 H). 13C NMR (50 MHz, CDCl3): d = 161.3, 158.8, 154.5,
148.8, 139.7, 131.4, 131.0, 129.6, 128.2, 127.2, 126.6,
125.0, 124.0, 123.2, 122.5, 120.3, 109.7, 108.1, 88.3, 86.0,
45.3, 41.8, 28.4, 28.2. UV (EtOH): lmax (log e) = 373.0
(3.99), 328.5 (4.19), 315.5 (1.32), 265.0 (1.62), 228.5 (2.21),
203.0 (2.03) nm. MS (70 eV): m/z (%) = 436 (100), 421 (34),
393 (10,6), 341 (8.7), 325 (42), 297 (10), 218 (9), 140 (11),
41 (22).
density(calcd): 1.367 mg/m3; absorption coefficient: 0.088
mm–1; F(000): 460; crystal size: (0.086 × 0.150 × 0.240)
mm3; q range for data collection: 2.29–27.42°; index ranges:
–6 ≤ h ≤ 6, –12 ≤ k ≤ 11, –26≤ l ≤ 25; reflections collected:
4349; independent reflections: 4219 [R(int) = 0.060];
completeness to q = 27.42°: 98.7%; absorption correction:
none; refinement method: full-matrix least-squares on F2;
data/restraints/parameters: 4219/2/365; goodness-of-fit on
F2: 1.077; final R indices [I > 2s(I)]: R1 = 0.0562,
wR2 = 0.1403; R indices (all data): R1 = 0.0803,
Spectroscopic Data of Compound 10
Orange crystals; mp 243–245 °C; yield 10%. IR (KBr):
3094, 2973, 2920, 2850, 1667, 1611, 1597, 1584, 1529,
1459, 1446, 1365, 1348, 1316, 1282, 1255, 1158, 1117,
1087, 760, 720, 701 cm–1. 1H NMR (200 MHz, CDCl3):
d = 9.0 (d, 1 H), 8.3 (d, 1 H), 8.1 (m, 2 H), 7.6 (m, 4 H), 3.3
(t, 2 H), 3.1 (t, 2 H), 2.0 (m, 4 H), 1.6 (s, 12 H). 13C NMR (50
MHz, CDCl3): d = 168.2, 155.2, 147.8, 147.2, 141.5, 130.7,
129.6, 129.6, 126.5, 125.8, 125.4, 125.0, 123.9, 123.0,
122.8, 121.7, 121.3, 109.5, 106.9, 76.8, 74.7, 32.2, 31.7,
26.6, 26.3, 22.8, 18.4. UV (EtOH): lmax (log e) = 364 (4.01),
306 (4.62), 230 (4.67) nm. MS (70 eV): m/z (%) = 464 (5),
408 (2), 352 (2), 44 (13), 40 (100).
wR2 = 0.1662; largest diff. peak and hole: 0.305 and –0.343
e Å–3.
(12) Melting points were obtained on Thomas Hoover and are
uncorrected. Analytical grade solvents were used. Column
chromatography was performed on silica gel (Acros
Organics 0.035–0.070 mm, pore diameter ca 6 nm). Infrared
spectra were recorded on a Perkin-Elmer FT-IR
spectrometer. 1H and 13C NMR were recorded at r.t. using a
Varian Gemini 200, in the solvents indicated, with TMS as
internal standard. Chemical shifts (d) are given in ppm.
Electron-impact mass spectra (70 eV) were obtained using a
VG Autospec apparatus (Micromass, Manchester, UK). The
main fragments were described as a relation between atomic
mass units and the charge (m/e) and the relative abundance
(13) (a) Pinto, M. C. F. R.; Pinto, A. V.; Oliveira, C. G. T. An.
Acad. Bras. Cien. 1980, 52, 481. (b) Hooker, S. C. J. Am.
Chem. Soc. 1936, 58, 1181.
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