New adducts of lapachol with primary amines

Article abstract of DOI:10.1590/S0103-50532011000400025

New adducts of lapachol with neat primary aliphatic amines were obtained in a solvent-free reaction in good to reasonable yields (52 to 88percent), at room temperature. The new compounds containing a phenazine moiety were obtained from suitable functionalized aminoalkyl compounds, including ethanolamine, 3-propanolamine, 2-methoxy-ethylamine, 3-methoxy-propylamine, n-butylamine and 2-phenetylamine. ?2011 Sociedade Brasileira de Qui?mica.

Full text of DOI:10.1590/S0103-50532011000400025

J. Braz. Chem. Soc., Vol. 22, No. 4, 796-800, 2011.
Printed in Brazil - ©2011 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Short Report
S
New Adducts of Lapachol with Primary Amines
Mirelly D. F. Santos, José T. Litivack-Junior, Roberto V. Antunes, Tania M. S. Silva and
Celso A. Camara*
Departamento de Química, Universidade Federal Rural de Pernambuco, Campus Dois Irmãos,
52171-900 Recife-PE, Brazil
A reação do lapachol à temperatura ambiente, com aminas alifáticas primárias forneceu
novos adutos identificados como derivados do núcleo fenazina. Os produtos foram obtidos em
rendimentos bons a razoáveis (52 a 88%), a temperatura ambiente e sem o uso de solvente, a partir
da reação com alquilaminas funcionalizadas, como n-butilamina, etanolamina, 3-propanolamina,
2-metoxi-etilamina, 3-metoxi-propilamina e 2-feniletilamina.
New adducts of lapachol with neat primary aliphatic amines were obtained in a solvent-free
reaction in good to reasonable yields (52 to 88%), at room temperature. The new compounds
containing a phenazine moiety were obtained from suitable functionalized aminoalkyl compounds,
including ethanolamine, 3-propanolamine, 2-methoxy-ethylamine, 3-methoxy-propylamine,
n-butylamine and 2-phenetylamine.
Keywords: phenazines, lapachol, nitrogen adducts, quinones, 1,4-naphthoquinone
Introduction
in which the cascade of one-electron radical enzymatic-
mediated reactions results in the formation of superoxide
radical anions, responsible for cellular damage in living
media.9 In a continuing work concerning the reactivity
of lapachol and related quinones,10,11 we now present
our results concerning the reaction of lapachol with
primary aliphatic amines. This smooth reaction conduced
to new adducts with a cyclic structure consisting of
a phenazine nucleus.12 Our initial observation, unlike
previous reports,13 is that lapachol 1 is almost entirely
consumed when mixed with primary amines, like
n-butylamine, ethanolamine, 3-hydroxypropylamine,
2-methoxyethylamine, 3-methoxypropylamine, and
2-phenylethylamine. The reaction of some few secondary
cyclic amines with lapachol have also been described
previously, with some unusual spectroscopic data found.14
Molecules containing a quinone moiety as a structural
component constitute an important class of compounds
in organic chemistry. The conjugated 1,4-dicarbonyl or
1,2-dicarbonyl moiety is responsible for a characteristic
reactivity behavior, yielding a somewhat particular
chemistry repertoire for these compounds. These
functional groups are also involved in numerous biological
activities, mostly cytotoxic ones. The wide range of
biological activities includes anticancer,1 inhibitors of
topoisomerase II,2 highlighting their use as valuable
candidates in neglected tropical diseases, including
leishmaniasis,3 tuberculosis4 and tripanosomiasis.5 Among
the naturally occurring naphthoquinones in Tabebuia spp,
lapachol, a-lapachone and b-lapachone and xyloidones
are the most abundant and studied compounds in these
and related species.6 b-Lapachone, in particular, showed
a more defined and impressive biological profile in anti-
tumor screenings than the regioisomer a-lapachone or
lapachol.7,8 The molecular mechanism involved in the
observed antitumoral and cytotoxic activities of these
compounds seems to be mainly related to the ability of
the quinone nucleus in participating in redox processes,
Results and Discussion
The products were formed in reactions at room
temperature, using solvent-free conditions with neat
amines, proceeding slowly within 24-48 h to give polar dye
compounds. These presented as crystals with brilliant green
color when in solid form, and deep-blue when in solution
with polar solvents. These compounds were identified by
usual spectroscopic methods as presenting the structure
*e-mail: ccelso@dq.ufrpe.br

Vol. 22, No. 4, 2011
Santos et al.
797
2a-f shown, as an adduct of two molecules of lapachol
with the corresponding amine (Scheme 1). The synthesis
of compounds containing this type of phenazine nucleus
was described previously for the reactions with aromatic
amines.12 The previously described conditions in the
cited literature includes thermal treatment of the reaction
mixtures. The present work extends this methodology to a
more environmentally benign procedure, with reasonable to
good yields (52-88%) of products in good purity, with easy
isolation and reproducibility. The reaction was conducted in
an open vessel, based on the experimental observation that
the reaction proceeds faster in the presence of molecular
oxygen. A closed sample in inert gas remains a blue
liquid for a very long time, and, when opened, an instant
precipitation of green crystals is observed in the flask.
The procedure of isolation consists in filtering the formed
crystals at vacuum followed by water washing with some
methanol added. The crystals obtained are sufficiently pure
to TLC inspection and spectrometric analysis. Attempts
to recrystalize in different solvent mixtures results in
decomposition of the starting material, as observed by
TLC. Although the detailed mechanism for this reaction
remains to be further clarified, a lot of precedent data is
available to clarify some points. The nucleophilic addition
of amines to carbonyl of quinone nucleus is a known
reaction, although the subsequent reactions of the formed
adducts are characteristic of quinone chemistry.15 These
hydroxyquinone adducts on the carbonyl with amines can
undergo a reaction called Strecker degradation,16 rather
than the conventional Schiff’s base addition followed by
water elimination product. These alternative path probably
consists in an imine-enamine isomerization, followed by
hydrolysis in situ with formal dealkylation of the primary
amine adduct. Recently the reaction of 2-hydroxy-1,4-
naphthoquinone (lawsone) with primary amino acids was
described as a new class of fingermark detection reagents.15
It is noteworthy that in the cited work the best profile for
fingermark detection was achieved with the amino acid
lysine. On the basis of our findings, we believe that this
is due to the presence of a more nucleophylic amino alkyl
side chain residue. The authors in this work did not support
the proposed adducts with any kind of experimental data;
no attempts for isolation were made or spectroscopic
characterization of products furnished. Additionally, the
fluorescence emission spectra of some of the adducts
reported here are in agreement with the profile previously
reported by Jelly et al.15 (see supplementary information,
SI, Figure S25). However, in opposition with the structure
furnished by Jelly et al.,15 the elemental microanalysis
is consistent with the presence of two nitrogen atoms
(see Experimental section), with just one alkyl residue
from the amine, supporting a phenazine nucleus. Another
observation concerns the extremely low reactivities of
amino acids as glycine and phenylalanine. These amino
acids, even in the presence of some inorganic and organic
basis, reacts very slowly furnishing complex mixtures at
TLC inspection. We also were unable to isolate some useful
products from the reaction of lapachol with benzylamine.
At the same conditions listed above, the reaction proceeds
rapidly with a prolific profile of by-products, and attempts
to purification by column chromatography were also
unsuccessful. A proposed mechanism for the formation of
(2) from (1) is presented in Figure 1. The characterization
1
of 2a by H and 13C NMR analysis showed a simplified
spectra, attributed to the assumption of canonical equivalent
resonance forms on the proposed structure (Figure 1). A
singlet at 1.79 ppm (6H) and a doublet at 1.62 ppm (0.5 Hz,
6H) were attributed to methyl signals of the prenyl side
chain. The methyl groups are coupled with the vinylic
proton at 5.31 ppm (m, 2H), and the vinylic proton coupled
with the allylic methylene which appear at 3.47 ppm (m,
4H, 7 Hz). The aromatic protons are two double doublets
at 8.69 ppm (2H, 8/0.5 Hz) and 8.16 ppm (2H, 8/0.5 Hz),
attributed to the ortho hydrogens relative to quinone/
phenazine nucleus. The other two meta hydrogens absorbs
as a double of double doublets at 7.60 (2H, 0.5/1/8 Hz)
and 7.40 ppm (2H, 0.5/1/8 Hz). The methylene attached
to nitrogen appears as a triplet at 2.84 ppm (2H, 5.5 Hz),
and couples with another carbynolic methylene as a triplet
at 3.56 ppm (2H, 5.5 Hz).
R =
OH
R
O
(2a) CH2OH (88%)
(2b) CH2OCH3 (52%)
(2c) CH2CH2OH (80%)
(2d) CH2CH2OCH3 (58%)
(2e) CH2CH2CH3 (77%)
(2f) CH2Ph (58%)
R
NH2
OH
N
O
r.t., neat
N
O
(1)
Scheme 1. Reaction of lapachol adducts with primary neat alkyl amines.

798
New Adducts of Lapachol with Primary Amines
J. Braz. Chem. Soc.
O
O
O
R
R
R
HO
H
HO
HO
R'CH2NH2
OH
OH
N+
(1)
OH
N+
R'
O
R'
N
O
R'
O
O
R'CH2HN
OH
OH
OH
OH
R
OH
R
−H2O
R
R
R
O
OH
O
(1)
O
R
O
R
OH
OH
R
HO
HOH
−H2O
−H2O
OH
OH
N
HN
N
R
N
−R'CHO
OH
OH
NCH2R'
NH2CH2R'
NHCH2R'
OH
O
R
R
R
R
OH
OH
OH
OH
OH
R
OH
R
O
R
−H2O
N
N
O
N
NCH2R'
NCH2R'
NCH2R'
OH
R
R= CH2CH=C(CH3)2
R'= any alkyl side chain
R
R
OH
OH
(2)
(2)
Figure 1. A proposed mechanism for the formation of (2) from (1) and the tautomerism in phenazine adducts (2)
Conclusions
for 1H and 50.3 MHz for 13C, with DMSO-d6 as solvents,
and HR mass spectra, on a VG Autospec spectrometer
(electron-impact at 70 eV). The reaction progress was
monitored using thin layer chromatography on a silicagel
UV254 TLC aluminum sheet. The elemental analysis was
performed on a CE EA1110 instrument at the Central
Analítica (Departamento de Química Fundamental -
Universidade Federal de Pernambuco).
In the present study, we presented a new, simple and
solvent-free procedure for the reaction of lapachol with
primary amines at ambient temperature. The obtained
yields were good to reasonable and reproducible, furnishing
new derivatives of phenazines from lapachol, with suitable
functionalized amines.
Experimental
General procedure for the synthesis of adducts 2a-f
General
A solution of lapachol 1 (0.5 g) and corresponding
amine (1 mL) was stirred in an open flask, for a 48 h period
at room tempertaure. The initially yellow solution turned
to deep red, and finally to a greenish-blue precipitated
material, or deep-blue solution with crystals was obtained.
TLC inspection of the reaction mixture showed an almost
complete consumption of lapachol after 48 h. With the aid
of water with some methanol (5%), the solids were filtered
in vacuum, washed with additional water, dried at room
temperature as fluorescent green or deep blue crystals.
Unless otherwise stated, all common reagents and
solvents were used as obtained from commercial suppliers
without further purification. Lapachol was previously
obtained by usual methods. Melting points were obtained
from an electrically heated metal block apparatus (Quimis),
and were not corrected. FTIR spectra were obtained in
a Bomen-Michelson spectrophotometer using KBr film.
NMR spectra were recorded in aVarian-Mercury 200 MHz

Vol. 22, No. 4, 2011
Santos et al.
799
9-Hydroxy-7-(2-hydroxyethyl)-6,8-bis(3-methylbut-
2-enyl)dibenzo[a,j]phenazin-5(7H)-one (2a): 88% yield,
deep blue crystals with mp 281-3 oC; IR (KBr) nmax/cm-1:
3200, 3058, 2962, 2910, 2852, 1608, 1570, 1508, 1409,
1126, 1028, 789; UV (EtOH) λmax/nm: 650, 627, 528, 287;
1H NMR (DMSO-d6, 200 MHz) d 1.62 (s, 6H), 1.79 (s,
6H), 2.84 (t, 2H, J 5.5 Hz), 3.47 (m, 4H, J 7 Hz), 3.56 (t,
2H, J 5.5 Hz), 5.31 (m, 2H), 7.40 (ddd, 2H, J 7/1/1 Hz),
7.60 (ddd, 2H, J 7/1/1 Hz), 8.16 (dd, 2H, J 8/0.5 Hz), 8.69
(dd, 2H, J 8/0.5 Hz); 13C NMR (APT, DMSO-d6, 50 MHz)
d 17.9, 21.7, 25.5, 41.2, 57.5, 111.2, 121.7, 122.0, 123.5,
124.9, 128.7, 129.3, 130.0, 131.7, 148.4, 176.8. Elemental
analysis for C32H32N2O3.H2O found: C, 72.89; H, 7.39; N,
5.41; Requires: C, 72.70; H 6.86; N, 5.30%.
(d, 4H, J 6.6 Hz), 5.30 (m, 2H), 7.41 (dd, 2H, J 8/8 Hz),
7.61 (dd, 2H, J 8/8 Hz), 8.17 (d, 2H, J 8 Hz), 8.70 (d, 2H,
J 8 Hz); 13C NMR (APT, DMSO-d6, 50 MHz) d 18.0, 21.8,
25.5, 26.5, 37.0, 58.0, 68.9, 111.3, 121.7, 122.1, 123.5,
125.0, 128.8, 129.4, 130.1, 131.8, 148.5, 176.9; Elemental
analysis for C34H38N2O4.2H2O found: C, 71.18; H, 7.61; N,
5.02; Requires: C, 71.06; H, 7.37; N, 4.87%.
7-Butyl-9-hydroxy-6,8-bis(3-methylbut-2-enyl)
dibenzo[a,j]phenazin-5(7H)-one (2e): 80% yield of a
greenish blue solid with mp 276-9 oC; IR (KBr) nmax/cm-1:
3400, 2920, 2854, 1585, 1508, 1477, 1454, 1415, 1300,
1249, 1157, 1118; UV (EtOH) λmax/nm: 650, 622, 524,
284, 250, 245; 1H NMR (DMSO-d6, 200 MHz) d 0.84 (t,
3H, J 7 Hz), 1.30 (m, 2H), 1.48 (m, 2H), 1.63 (s, 6H), 1.79
(s, 6H), 2.76 (t, 2H, J 7 Hz), 3.48 (m, 4H), 5.31 (m, 2H),
7.41 (dd, 2H, J 6.8/6.2 Hz), 7.61 (dd, 2H, J 6.8/6.2 Hz),
8.18 (d, 2H, J 6.8 Hz), 8.70 (d, 2H, J 6.8 Hz); 13C NMR
(APT, DMSO-d6, 50 MHz) d 13.4, 17.9, 19.1, 21.8, 25.5,
29.1, 38.6, 111.2, 121.7, 122.1, 123.5, 124.9, 124.9, 128.7,
129.3, 130.0, 131.7, 148.4, 176.8; Elemental analysis
for C34H38N2O3.H2O found C, 75.81; H, 7.87; N, 5. 14;
Requires: C, 75.53; H, 7.46; N, 5.18%.
9-Hydroxy-7-(2-methoxyethyl)-6,8-bis(3-methylbut-
2-enyl)dibenzo[a,j]phenazin-5(7H)-one (2b): 52% yield,
greenish blue crystals with mp 206-8 oC; IR (KBr) nmax/cm-1:
3360, 2920, 2910, 1654, 1570, 1508, 1485, 1115, 759; UV
(EtOH) λmax/nm: 648, 622, 522, 280; 1H NMR (DMSO-d6,
200 MHz) d 1.62 (s, 6H), 1.69 (s, 6H), 2.96 (m, 2H), 3.25
(s, 3H), 3.48 (m, 4H), 5.31 (m, 2H), 7.42 (dd, 2H, J 7/7.8
Hz), 7.61 (dd, 2H, J 7/7.8 Hz), 8.18 (d, 2H, J 7.8Hz), 8.70
(d, 2H, J 7.8 Hz); 13C NMR (APT, DMSO-d6, 50 MHz) d
17.9, 21.8, 25.5, 58.1, 68.2, 111.3, 121.7, 122.2, 123.5,
125.2, 128.7, 129.3, 130.1, 131.7, 148.4, 176.6; Elemental
analysis for C33H34N2O3.3H2O found: C, 69.61; H, 6.67; N,
4.14; Requires C, 70.44; H, 6.67; N, 4.98%.
9-Hydroxy-6,8-bis(3-methylbut-2-enyl)-7-
phenethyldibenzo[a,j]phenazin-5(7H)-one (2f): 62% of a
greenish blue crystals with mp 217-9 oC; IR (KBr) nmax/cm-1:
2890, 2920, 1564, 1509, 1474, 1374, 1299, 1250, 1161,
1
1128; UV (EtOH) λmax/nm: 650, 622, 524, 284, 250; H
9-Hydroxy-7-(3-hydroxypropyl)-6,8-bis(3-methylbut-2-
enyl)dibenzo[a,j]phenazin-5(7H)-one (2c): 84% yield as a
greenish blue solid with mp 251-3 ºC; IR (KBr) nmax/cm-1:
NMR (DMSO-d6, 200 MHz) d 1.61 (s, 6H), 1.78 (s, 6H),
2.83 (dd, 2H, J 6.2/5.4 Hz), 3.03 (dd, 2H, J 6.2/5.4 Hz), 3.47
(d, 4H, J 6.2 Hz), 5.30 (m, 2H), 7.28 (m, 5H), 7.40 (ddd,
2H, J 1.2/6.8/8.2 Hz), 7.61 (ddd, 2H, J 1.2/6.8/8.2 Hz),
8.16 (dd, 2H, J 1.2/6.8 Hz), 8.69 (dd, 2H, J 1.2/6.8 Hz); 13C
NMR (APT, DMSO-d6, 50 MHz) d 17.9, 21.8, 25.5, 36.2,
38.2, 111.4, 121.7, 122.4, 123.4, 124.9, 125.0, 126.7, 128.1,
128.3, 128.4, 128.6, 128.7, 128.8, 128.2, 130.1, 131.7,
148.3, 178.5; Elemental analysis for C38H38N2O3.2H2O
found: C, 74.84; H, 7.16; N, 4.30; Requires: C, 75.22; H,
6.98; N, 4.62%.
3414, 2924, 1620, 1570, 1485, 1458, 1100, 779; UV (EtOH)
1
λ
max/nm: 650, 622, 528, 287; H NMR (DMSO-d6, 200
MHz) d 1.55, (s, 6H), 1.62 (m, 2H), 1.72 (s, 6H), 2.79 (t,
2H, J 7 Hz), 3.42 (m, 6H), 5.24 (m, 2H), 7.35 (ddd, 2H,
J 1/8/8 Hz), 7.54 (ddd, 2H, J 1/8/8 Hz), 8.11 (d, 2H, J 8
Hz), 8.63 (d, 2H, J 8 Hz); 13C NMR (APT, DMSO-d6, 50
MHz) d 17.9, 21.8, 25.5, 30.1, 36.9, 58.0, 111.4, 121.8,
122.4, 123.5, 124.9, 125.1, 128.7, 129.3, 130.1, 131.7,
148.4, 176.6; Elemental analysis for C33H36N2O4.H2O
found: C, 72.90; H, 7.40; N, 5.00; Requires: C, 73.04; H,
7.06; N, 5.16%.
Supporting Information
Supplementary information (Figures S1-S25) is
available free of charge at http://jbcs.sbq.org.br, as a PDF
file.
9-Hydroxy-7-(3-methoxypropyl)-6,8-bis(3-methylbut-2-
enyl)dibenzo[a,j]phenazin-5(7H)-one (2d): 58% yield as a
greenish blue solid with mp 242-4 oC; IR (KBr) nmax/cm-1:
3300, 2958, 2920, 1620, 1570, 1554, 1485, 1280, 1249,
1185, 1130; UV (EtOH) λmax/nm: 650, 622, 528, 290; 1H
NMR (DMSO-d6, 200 MHz) d 1.62 (s, 6H), 1.78 (s, 6H),
1.78 (m, 2H), 2.81 (m, 2H), 3.19 (s, 3H), 3.35 (m, 2H), 3.48
Acknowledgments
We are very grateful to Dr. Eduardo Oliveira (LTF-
UFPB) for the critical revision of the original manuscript

800
New Adducts of Lapachol with Primary Amines
J. Braz. Chem. Soc.
and useful suggestions. Finnancial support from the
Coordenação de Aperfeiçoamento do Pessoal de Nível
Superior (CAPES), and Fundação de Amparo à Pesquisa
do Estado de Pernambuco (FACEPE) are gratefully
acknowledged. We also thank the Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq-Brazil),
and Analytical Center of LTF-UFPB, DQ-UFPE and
CENAPESQ-UFRPE.
8. Silva, M. N.; Ferreira, V. F.; Souza, M. C. B. V.; Quim. Nova,
2003, 26, 407.
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M. D.; Pinto, A. C. ; Echevarria, A.; Braz. J. Med. Biol. Res.
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J. Braz. Chem. Soc., Vol. 22, No. 4, S1-S13, 2011.
Printed in Brazil - ©2011 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Supplementary Information
SI
New Adducts of Lapachol with Primary Amines
Mirelly D. F. Santos, José T. Litivack-Junior, Roberto V. Antunes, Tania M. S. Silva and
Celso A. Camara*
Departamento de Química, Universidade Federal Rural de Pernambuco, Campus Dois Irmãos,
52171-900 Recife-PE, Brazil
Figure S1. 1H NMR spectrum (DMSO-d6, 200 MHz) of 2a.
*e-mail: ccelso@dq.ufrpe.br

S2
New Adducts of Lapachol with Primary Amines
J. Braz. Chem. Soc.
Figure S2.. 1H NMR expansion spectrum (DMSO-d6, 200 MHz) of 2a.
Figure S3. 13C NMR (APT) spectrum (DMSO-d6, 50 MHz) of 2a.

Vol. 22, No. 4, 2011
Santos et al.
S3
Figure S4. 13C NMR (APT) spectrum expansion (DMSO-d6, 50 MHz) of 2a.
Figure S5. HMQC spectrum of 2a.

S4
New Adducts of Lapachol with Primary Amines
J. Braz. Chem. Soc.
Figure S6. COLOC spectrum of 2a.
Figure S7. Infrared spectrum (KBr, cm-1) of 2a.

Vol. 22, No. 4, 2011
Santos et al.
S5
Figure S8. 1H NMR spectrum (DMSO-d6, 200 MHz) of 2b.
Figure S9. 13C NMR (APT) spectrum (DMSO-d6, 50 MHz) of 2b.

S6
New Adducts of Lapachol with Primary Amines
J. Braz. Chem. Soc.
Figure S10. Infrared spectrum (KBr, cm-1) of 2b.
Figure S11. 1H NMR spectrum (DMSO-d6, 200 MHz) of 2c.

Vol. 22, No. 4, 2011
Santos et al.
S7
Figure S12. 13C NMR (APT) spectrum (DMSO-d6, 50 MHz) of 2c.
Figure S13. Infrared spectra (KBr, cm-1) of 2c.

S8
New Adducts of Lapachol with Primary Amines
J. Braz. Chem. Soc.
Figure S14. 1H NMR spectrum (DMSO-d6, 200 MHz) of 2d.
Figure S15. 1H NMR spectrum expansion (DMSO-d6, 200 MHz) of 2d.

Vol. 22, No. 4, 2011
Santos et al.
S9
Figure S16. 13C NMR (APT) spectrum (DMSO-d6, 50 MHz) of 2d.
Figure S17. Infrared spectrum (KBr, cm-1) of 2d.

S10
New Adducts of Lapachol with Primary Amines
J. Braz. Chem. Soc.
Figure S18. 1H NMR spectrum (DMSO-d6, 200 MHz) of 2e.
Figure S19. 1H NMR spectrum expansion (DMSO-d6, 200 MHz) of 2e.

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Figure S20. 13C NMR (APT) spectrum (DMSO-d6, 50 MHz) of 2e.
Figure S21. Infrared spectrum (KBr, cm-1) of 2e.

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New Adducts of Lapachol with Primary Amines
J. Braz. Chem. Soc.
Figure S22. 1H NMR spectrum (DMSO-d6, 200 MHz) of 2f.
Figure S23. 13C NMR (APT) spectrum (DMSO-d6, 50 MHz) of 2f.

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Figure S24. Infrared spectrum (KBr, cm-1) of 2f.
Figure S25. Fluorescence spectra (excit 590 nm) of lapachol adducts (2).