3,3′-(Arylmethylene)bis(2-hydroxynaphthalene-1,4-dione) as the main product of the Mannich reaction of 2-hydroxy-1,4-naphthoquinone with 4H-1,2,4-triazol-4-amine and various aldehydes

Article abstract of DOI:10.3184/174751918X15242406216491

The Mannich reaction of lawsone with various aldehydes and 4H-1,2,4-triazol-4-amine gave unexpected 3,3′-(arylmethylene)bis(2-hydroxynaphthalene-1,4-dione)derivatives.With2,4-dihydroxybenzaldehydeunderthesameconditions,itledtotheformationof3-hydroxy-12-(3

Full text of DOI:10.3184/174751918X15242406216491

224 RESEARCH PAPER
VOL. 42 APRIL, 224–226
JOURNAL OF CHEMICAL RESEARCH 2018
3
,3′-(Arylmethylene)bis(2-hydroxynaphthalene-1,4-dione) as the main product
of the Mannich reaction of 2-hydroxy-1,4-naphthoquinone with 4H-1,2,4-
triazol-4-amine and various aldehydes
Razieh Ghodsi *, Morteza Safarnejad , Sina Omid Malayeri and Sima Golmakanion
a,b
b
b
b
a
Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
b
The Mannich reaction of lawsone with various aldehydes and 4H-1,2,4-triazol-4-amine gave unexpected 3,3′-(arylmethylene)bis(2-
hydroxynaphthalene-1,4-dione)derivatives.With2,4-dihydroxybenzaldehydeunderthesameconditions,itledtotheformationof3-hydroxy-12-
(3-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-6H-benzo[b]xanthene-6,11(12H)-dione instead of various triazolylaminonaphthoquinones.
Keywords: Mannich reaction, 2-hydroxynaphthalene-1,4-dione (lawsone), 4H-1,2,4-triazol-4-amine, 3,3′-(arylmethylene)bis(2-hydroxy-
naphthalene-1,4-dione), benzo[b]xanthene-6,11(12H)-dione
Interest in the organic synthesis of molecules possessing the
quinone structure has increased in recent years because of their
biological properties, including antitumour. anti-inflammatory,
molluscicidal, leishmanicidal, trypanocidal and antifungal
the compound thus synthesised was 3,3′-(arylmethylene)bis(2-
hydroxynaphthalene-1,4-dione) instead. Before characterising
the exact structures of our products, we compared the NMR
and mass spectra of our compounds with those of Fiorot’s
1–6
11
activities. 1,4-Naphthoquinones are widely distributed in
nature, and many clinically important antitumour drugs having
a quinone moiety, such as mitoxantrones, anthracyclines
compounds. Interestingly, the NMR spectrum of one of
our compounds synthesised from 4-methoxybenzaldehyde
was the same as the compound that Fiorot et al. synthesised
using this aldehyde, 4-nitroaniline and lawsone. Also, the
mass of the compound they reported is that of the [M-H] of
3′-[(4-methoxyphenyl) methylene]bis(2-hydroxynaphthalene-
14-dione) and not of the product they expected. In addition,
the melting points of our compound and that of Fiorot and co-
workers were identical. The melting points and IR and NMR
data of our products are the same as those of the products that
7
and saintopin, display excellent anticancer activities.
2
-Hydroxynaphthalene-1,4-dione (lawsone) is a red-orange dye
present in the leaves of the henna plant, which is traditionally
used for colouring hair and dying nails and skin and as a starting
8
material for the development of new bioactive compounds.
Someauthorshavereportedthesynthesisofaminonaphthoquinone
by a one-pot reaction of 2-hydroxynaphthalene-1,4-dione aromatic
aldehydes and aromatic amines in the presence of different
13
14
Oliveira et al. and Tisseh et al. reported in their synthesis
of 3,3′-(arylmethylene)bis(2-hydroxynaphthalene-1,4-dione) or
bisnaphthoquinones derivatives.
9
catalysts and solvents. Dabiri et al. reported the synthesis of
2-hydroxy-1,4-naphthoquinone derivatives using the Mannich
reaction in water under reflux in the presence of indium chloride
as a catalyst. Shaterian et al. have recently described the use
In order to accomplish the synthesis of the desired
triazolylaminonaphthoquinones (Scheme 1), we first allowed
4H-1,2,4-triazol-4-amine1(1.0 mmol)and4-hydroxybenzaldehyde
2f (1.0 mmol) to combine in ethanol under reflux to produce various
imines 3, following the formation of these imines by TLC and, after
completion of imine formation, adding lawsone 4 (1.0 mmol) and
TFA (20 mol%) to react in ethanol under reflux (Table 1, entry 1)
to yield bisnaphthoquinone, or 3,3′-[(4-hydroxyphenyl)methylene]
bis(2-hydroxynaphthalene-1,4-dione). The above three-component
condensation was then tried with InCl3, p-toluenesulfonic
acid (p-TSA) and AcOH instead of TFA in ethanol, but the
desired triazolylaminonaphthoquinone 5 did not result. Saluja
10
of ionic liquids as catalysts in the Mannich reaction of lawsone
11
with various aldehydes and amines. Recently, Fiorot et al. used
p-TsOH as a catalyst in the multicomponent Mannich reaction of
lawsone with p-nitroaniline and of pyrrolidine with some aromatic
12
aldehydes in acetonitrile at room temperature. Saluja et al. have
also reported the synthesis of naphthoquinone–urazole hybrids via
a one-pot condensation of lawsone, aldehydes and 4-phenylurazole
employing a task-specific ionic liquid (bmim[HSO ]).
4
We have designed some triazolylaminonaphthoquinones as
anticancer agents, and we have used 4H-1,2,4-triazol-4-amine
aromatic aldehydes and lawsone to synthesise them via the
Mannich reaction in ethanol under reflux in the presence of a
catalytic amount of trifluoroacetic acid (TFA). The aim of this
study was to examine the application of TFA for the one-pot
synthesis of our desired triazolylaminonaphthoquinones.
12
et al. also reported that a reaction of 4-chlorobenzaldehyde,
lawsone and 4-phenylurazole in the presence of InCl or other
3
Lewis acid catalyst, such as CAN, CeCl3 or La(OTf) , in
3
ethanol under reflux gave only the bisnaphthoquinone and
not their targeted aminonaphthoquinone. Surprisingly, using
2
,4-dihydroxybenzaldehyde under the same conditions led
Results and discussion
to the formation of 3-hydroxy-12-(3-hydroxy-1,4-dioxo-1,4-
dihydronaphthalen-2-yl)-6H-benzo[b]xanthene-6,11(12H)-dione
instead of the symmetric 3,3-[(2,4-dihydroxyphenyl)methylene]
bis(2-hydroxynaphthalene-1,4-dione).
The formation of this product probably occurs through
nucleophilic addition of 2-hydroxy-1,4-naphthoquinone to
the resulting aminonaphthoquinone in the acidic medium.
The molecular structure was confirmed by IR and NMR
data. We did not investigate the exact mechanism of this
reaction, but a possible mechanism for the formation of the
According to the mechanism of the Mannich reaction of
lawsone with aldehydes and amines that Dabiri et al.
10
proposed, and also for preventing side reactions, we first
allowed 4H-1,2,4-triazol-4-amine to combine with various
aromatic aldehydes in ethanol under reflux to produce the
imines 3. The formation of these imines was followed by thin-
layer chromatography (TLC), and, following completion of
imine formation, lawsone was added to the reaction mixture,
as shown in Scheme 1. The NMR data showed, however, that
*
Correspondent. E-mail: ghodsir@mums.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2018 225
N
N
N
N
O
NH2
R1
R3
N
H
a
R2
R1
R3
N
N
R2
3
1
2
1
2
3
2
2
2
2
2
2
2
a, R =F, R =R =H
1
2
3
b, R =CN, R =R =H
c, R =OCH , R =R =H
O
O
b
1
2
3
OH
3
1
2
3
d, R =NO , R =R =H
e, R =R =R =H
2
1
2
3
1
2
3
f, R =OH, R =R =H
g, R =OH R =R =H
,
4
2
1
3
O
O
N
O
O
OH
HO
N
O
OH
N
NH OH
O
O
O
HO
O
3
O
R
R1
3
R
R2
R2
O
6
R1
5
7
1
2
3
6
6
6
6
6
6
6
a, R =F, R =R =H
b, R =CN, R =R =H
c, R =OCH , R =R =H
d, R =NO , R =R =H
e, R =R =R =H
f, R =OH, R =R =H
1
2
3
1
2
3
3
1
2
3
2
1
2
3
1
2
3
2
1
3
g, R =OH, R =R =H
Scheme 1 Reagents and conditions: (a) EtOH, reflux; (b) EtOH, TFA, reflux.
O
OH
O
N
O
O
O
N
OH
OH
O
N
N
N
O
OH
NH2 OH
O
N
O
N
O
O
R
TFA
HO
O
HO
O
R
Scheme 2 Proposed mechanism for the formation of bisnaphthoquinone derivatives.
Table 1 Reaction conditions for the synthesis of 6f
3,3′-(arylmethylene)bis(2-hydroxynaphthalene-1,4-dione)
shown in Scheme 2.
is
Entry
Catalyst Catalyst (mol%) Solvent Time (h) Yield of 6f (%)
1
2
3
4
5
TFA
20
20
20
20
20
EtOH
EtOH
Water
EtOH
EtOH
10
10
10
10
10
75
85
81
78
53
Conclusions
InCl3
InCl3
AcOH
p-TSA
In conclusion, 3,3′-(arylmethylene)bis(2-hydroxynaphthalene-
,4-dione) is a by-product, or the main product, in the Mannich
reaction of 2-hydroxy-1,4-naphthoquinone with different
1

226 JOURNAL OF CHEMICAL RESEARCH 2018
−
1
aldehydes and amines, usually when the amine contains an
electron-withdrawing group. With our product, the triazole ring
might act as a good leaving group in the acidic environment
produced by TFA following nucleophilic attack by 2-hydroxy-
m.p. 185–187 °C (decomposed); IR (KBr) (ν /cm ): 3070 (OH),
max
1
1667, 1639 (C=O); H NMR (300 MHz, DMSO-d ): δ (ppm) 5.65 (s,
6
1
7
H, CH), 6.41–6.45 (m, 2H), 6.88 (s, 1H ), 7.01–7.04 (d, 1H, J = 9 Hz),
.45–7.50 (t, 1H, J = 9 Hz), 7.60–7.65 (t, 1H, J = 9 Hz), 7.69–7.72 (d, 1H,
J = 9 Hz), 7.77–7.87 (m, 4H), 8.02–8.05 (dd, 1H, J = 6.6, J = 2.4), 9.45
1,4-naphthoquinone on the aminonaphthoquinone. The reaction
13
(
s, 1H); C NMR (75 MHz, DMSO-d ): δ (ppm) 67.49, 102.62, 112.79,
of lawsone with an aromatic aldehyde possessing a hydroxyl
group in the ortho position gave the novel benzo[b]xanthene-
6
1
1
23.45, 124.43, 125.20, 125.38, 125.66, 126.0, 126.09, 129.75, 130.69,
30.89, 131.54, 132.02, 133.88, 134.28, 134.69, 135.85, 139.67, 149.82,
51.54, 156.78, 178.74, 188.12, 183.58, 188.35; LC-MS (ESI): 451.1
6
,11-dione scaffold with potential biological activity.
1
(
+
M+1) ; Anal. calcd for C H O : C, 72.00; H, 3.13; found: C, 69.92;
Experimental
27 14 7
H, 3.28%.
All chemical reagents and solvents used in this study were purchased
from Merck AG or Aldrich Chemical. Melting points were determined
with a Thomas–Hoover capillary apparatus. IR spectra were acquired
using a Perkin Elmer Model 1420 spectrometer. A Bruker FT-
Acknowledgement
We are grateful to the Research Deputy of Mashhad University
of Medical Sciences for financial support of this research as
part of the thesis of Morteza Safarnejad.
4
00 MHz instrument (Brucker Biosciences USA) was used to acquire
1
H NMR spectra with tetramethylsilane (TMS) as internal standard.
Chloroform-D and DMSO-d were used as solvents. Coupling constant
Received 27 January 2018; accepted 13 April 2018
Paper 1805228
https://doi.org/10.3184/174751918X15242406216491
Published online: 23 April 2018
6
(
J) values were estimated in hertz (Hz), and spin multiplets are given
as s (singlet), d (doublet), t (triplet) or m (multiplet) in parts per million
ppm).
(
Synthesis of 6a–g and 7; general procedure
References
A mixture of amine (10.0 mmol) and aldehyde (10.0 mmol) was
1
2
3
4
5
6
E.R. de Almeida, A.A. da Silva Filho, E.R. dos Santos and C.A. Lopes. J
Ethnopharmacol., 1990, 29, 239.
A.F. dos Santos, P.A. Ferraz, F.C. de Abreu, É. Chiari, M.O. Goulart and
A.E.G. Sant’Ana. Planta Med., 2001, 67, 92.
A.F. dos Santos, P.A. Ferraz, A.V. Pinto, M.d.C. Pinto, M.O. Goulart and
A.E. Sant’Ana Int. J. Parasitol Re., 2000, 30, 1199.
S. Gafner, J.L. Wolfender, M. Nianga, H. Stoeckli-Evans and K.
Hostettmann. Phytochem., 1996, 42, 1315.
B.S. Samant and C. Chakaingesu. Bioorg. Med. Chem. Lett., 2013, 23,
1420.
M.J. Teixeira, Y.M. de Almeida, J.R. Viana, J.G. Holanda Filha, T.P.
Rodrigues, J.R. Prata, I.C. Coelho, V.S. Rao and M.M. Pompeu. Phytother
Res., 2001, 15, 44.
15
refluxed in ethanol . After completion of the imine synthesis reaction,
as monitored by TLC, 2-hydroxynaphthalene-1,4-dione and TFA (20
mol%) were added and the mixture refluxed overnight. The reaction
mixture was then filtered and washed with ethanol to give the pure
products 6a and 6c–g. Compounds 6b and 7 were purified by column
chromatography (chloroform:methanol, 95:5) and recrystallised from
ethanol.
3
,3′-[(4-Fluorophenyl)methylene]bis(2-hydroxynaphthalene-1,4-
dione) (6a): Orange powder; m.p. 194–195 °C (same as ref.16); Yield
3%.
7
3
,3′-[(4-Cyanophenyl)methylene]bis(2-hydroxynaphthalene-1,4-
7
8
9
V.K. Tandon, R.V. Singh, D.B. Yadav. Bioorg. Med. Chem. Lett., 2004, 14,
dione) (6b): Orange-yellow powder; m.p. 195–197 °C (same as ref.17);
2901.
Yield 63%.
A.K. Jordao, M.D. Vargas, A.C. Pinto, F.d.C. da Silva and V.F. Ferreira.
RSC Adv., 2015, 5, 67909.
M. Dabiri, Z.N. Tisseh and A. Bazgir. Dyes Pigm., 2011, 89, 63.
3
,3′-[(4-Methoxyphenyl)methylene]bis(2-hydroxynaphthalene-1,4-
dione) (6c): Yellow powder; m.p. 220–222 °C (same as ref.13); Yield
1%.
,3′-[(4-Nitrophenyl)methylene]bis(2-hydroxynaphthalene-1,4-
dione) (6d): Orange powder; m.p. 177–178 °C (same as ref.18); Yield
7%.
,3′-(Phenylmethylene)bis(2-hydroxynaphthalene-1,4-dione) (6e):
Yellow powder; m.p. 202–204 °C (same as ref.19); Yield 55%.
,3′-[(4-Hydroxyphenyl)methylene]bis(2-hydroxynaphthalene-1,4-
dione) (6f): Red powder; m.p. 175–177 °C (same as ref.19); Yield 62%.
,3′-[(3-Hydroxyphenyl)methylene]bis(2-hydroxynapthelene-1,4-
dione) (6g): Brown powder; m.p. 170–172 °C (same as ref.17); Yield
7%.
-Hydroxy-12-(3-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-
yl)-6H-benzo[b]xanthene-6,11(12H)-dione (7): Red-orange solid;
7
10 H.R. Shaterian and M. Mohammadnia. J. Mol. Liq., 2013, 177, 353.
1
1
R.G. Fiorot, J.F. Allochio Filho, T.M. Pereira, V. Lacerda, R.B. dos Santos,
W. Romão and S.J. Greco. Tetrahedron Lett., 2014, 55, 4373.
P. Saluja, J.M. Khurana, K. Nikhil and P. Roy. RSC Adv., 2014, 4, 34594.
A.S. de Oliveira, L.C. Llanes, R.J. Nunes, R.A. Yunes and I.M. Brighente.
Green Sustainable Chem., 2014, 4, 177.
3
12
3
8
1
3
14 Z.N. Tisseh and A. Bazgir. Dyes Pigm., 2009, 83, 258.
15 A. Darvishia, M. Zarei, M.R. Akhgar. Lett. Org. Chem., 2013, 10, 645
3
16
J.M. Khurana, A. Lumb, A. Chaudhary and B. Nand. J. Heterocycl. Chem.,
014, 51, 1747.
2
3
1
18
7
G. Brahmachari. ACS Sustain. Chem. Eng., 2015, 3, 2058.
H. Wang, Z. Wang, C. Wang, F. Yang, H. Zhang, H. Yue and L. Wang. RSC
Adv., 2014, 4, 35686.
6
3
19 G. Sharma, S. Chowdhury, S. Sinha, H.K. Majumder, S.V. Kumar. J.
Enzyme. Inhib. Med. Chem., 2014, 29, 185.