A simple and convenient method for synthesis of new aminonaphthoquinones derived from lawsone by catalytic multicomponent Mannich reaction

Article abstract of DOI:10.1016/j.tetlet.2014.06.031

A clean, efficient and facile one-pot protocol was developed for the synthesis of a series of new aminonaphthoquinones derived from 2-hydroxy-1,4-naphthoquinone (lawsone) by three-component Mannich reaction using catalytic amount of p-TsOH in CH₃CN, at room temperature. At the present work, we improved the yield and significantly reduced the reaction time for several Mannich reactions with different amine and aromatic aldehydes using a non-expensive, mild catalyst and suitable solvent.

Full text of DOI:10.1016/j.tetlet.2014.06.031

Tetrahedron Letters 55 (2014) 4373–4377
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple and convenient method for synthesis of new
aminonaphthoquinones derived from lawsone by catalytic
multicomponent Mannich reaction
Rodolfo G. Fiorot a, João F. Allochio Filho a, Thieres M. C. Pereira b, Valdemar Lacerda Jr. a,
Reginaldo B. dos Santos a, Wanderson Romão b, Sandro J. Greco a,
⇑
a Laboratório de Síntese Orgânica & Medicinal, Departamento de Química, Universidade Federal do Espírito Santo, Avenida Ferrari 514, Goiabeiras, Vitória/ES 29075-910, Brazil
b Laboratório de Petroleômica, Departamento de Química, Universidade Federal do Espírito Santo, Avenida Ferrari 514, Goiabeiras, Vitória/ES 29075-910, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A clean, efficient and facile one-pot protocol was developed for the synthesis of a series of new amino-
naphthoquinones derived from 2-hydroxy-1,4-naphthoquinone (lawsone) by three-component Mannich
reaction using catalytic amount of p-TsOH in CH3CN, at room temperature. At the present work, we
improved the yield and significantly reduced the reaction time for several Mannich reactions with differ-
ent amine and aromatic aldehydes using a non-expensive, mild catalyst and suitable solvent.
Published by Elsevier Ltd.
Received 10 May 2014
Revised 5 June 2014
Accepted 5 June 2014
Available online 12 June 2014
Keywords:
Multicomponent reaction
Catalytic Mannich reaction
Lawsone
Nitrogen-containing compounds are ubiquitous in nature and
many of them are biologically active. The nitrogen-containing units
of these molecules play important roles in their bioactivity (Fig. 1).
For the synthesis of these nitrogen-containing building blocks, the
Mannich reaction is one of the most common and convenient
routes.1
The science of organic synthesis is constantly enriched by the
improvement of synthetic methodologies. The paradigms of
organic synthesis have shifted from the traditional concept using
only chemical yield to define efficiency to one in which the eco-
nomic and ecological values are also considered.
Recently, multicomponent reactions (MCRs) have received con-
siderable interest among synthetic chemists for the construction of
complex molecules.2 MCRs usually show good atom economy.
When compared with conventional organic reactions, MCRs are
advantageous because they are highly convergent, requiring mini-
mal time and effort to achieve structural complexity. Thus, MCRs
are also considered green chemical processes.
Over the years, hundreds of MCRs have been reported in the lit-
erature. These reactions include imine-based MCRs (involving imi-
nes as a substrate or an intermediate), which have received
considerable attention in recent years.3 This sudden rise in the
popularity of imine-based MCRs may be due to two factors: (i)
the substrate-dependent reactivity of imines and (ii) the commer-
cial availability of several hundred amines and aldehydes, which
are required to access many imines, thus leading to diverse molec-
ular scaffolds. Therefore, imines are considered to be versatile
building blocks for diversity-oriented synthesis using MCRs. Imi-
nes primarily act as electrophiles in MCRs. Among these reactions,
the Mannich reaction is one of the most widely used three-
component reactions which utilizes a non-enolizable aldehyde, a
primary or secondary amine and an enolizable carbonyl com-
pound. The resulting b-amino carbonyl compounds are important
synthetic intermediates for various pharmaceuticals and natural
products and have found wide application in organic synthesis.
Molecules with the quinone structure constitute one of the
most interesting classes of compounds in organic chemistry
because of their biological properties, including antitumor, mollus-
cicidal, leishmanicidal, anti-inflammatory and antifungal activities
(Fig. 2),4 as well as their industrial applications and their synthetic
potential as intermediates to obtain heterocyclic compounds.
Considering the incorporation of amino groups or a nitrogen
atom into naphthoquinones often results in increased antican-
cer,5—molluscicidal6 and antibacterial activities,7 part of our pro-
gramme aimed at the synthesis of new aminonaphthoquinone
derivatives with potential biological activity. We are currently
investigating the synthesis of lawsone 1 derivatives via a simple
⇑
Corresponding author. Tel.: +55 27 3145 4514; fax: +55 27 4009 2826.
E-mail address: sandro.greco@ufes.br (S.J. Greco).
http://dx.doi.org/10.1016/j.tetlet.2014.06.031
0040-4039/Published by Elsevier Ltd.

4374
R. G. Fiorot et al. / Tetrahedron Letters 55 (2014) 4373–4377
O
OCH3
O
OH
HO
O
O
HO
H
CO2
HO
O
CH3
OH
+
O
OH
O
NH
Catlyst, rt
Solvent
N
N
H
HO
+ R2 NH2
H
OH
N
R1
H
N
CH3
NH3
OH
O
R2
OH
N
O
R
R1
CH3
Lawsone (1)
Nikkomycin B
or -N-R2 if secondary amine
O
Tramadol
(-)-Swainsonine
N
OR2
O
O
H3C
O
OH
NH
CH3
OH
Scheme 1. Synthesis of lawsone derivatives.
S
O
HN
O
Ph
HN
H3C
i-PrO2C
N
O
F
OH
O
R1
O
H
O
HO
O
SQ 32547
BzO
NH2
O
AcO
OH
OH
Paditaxel - R1 = Bz, R2 = Ac
F3C
Solvent
rt
H
+
+
H3CO
H
(-)-Cytoxazone
Docetaxel - R1 = Boc, R2 = H
N
O2N
O
O
1
NO2
NO2
Figure 1. Nitrogen containing bioactive compounds.
2
4
3
NO2
and atomically efficient three-component condensation reaction of
lawsone, aromatic aldehydes and aromatic and alicyclic amines in
the presence of a catalyst at room temperature (Scheme 1).
The Mannich reaction of lawsone was first described by Leffer
and Hathaway in 1948,8 and was performed because certain 2-
hydroxy-3-alkyl-1,4-naphthoquinone compounds had shown anti-
malarial activity. However, this methodology has not been widely
utilized to synthesis these molecules.
Scheme 2. Optimization of multicomponent Mannich reaction.
Table 1
Solvents screening for model reaction in Scheme 2a
Entry
Solvent/volumeb
Time (h)
Yield (%)
1
2
3
4
5
EtOH (10 mL)
H2O (5 mL)
CH3CN (3 mL)
Et2O (4 mL)
24
26
6
26
26
82
84
98
87
73
Our research group has recently described the use of the Man-
nich reaction to react lawsone with various aldehydes and amines
in ethanol at room temperature using the procedure described in
the literature, with minor modifications.9 It should be noted that
the reaction times range from 12 to 48 h depending on the alde-
hyde and the amine used. Subsequently, Dabiri and co-workers
published the synthesis of aminonaphthoquinones using the Man-
nich reaction in an aqueous medium under reflux using InCl3 as a
catalyst, and the reaction times varied from 4 to 7.5 h.10 Recently,
Shaterian and co-workers11 employed ionic liquids as catalyst in
multicomponent Mannich reaction derived from lawsone.
From our work on the development of the green Mannich reac-
tion, the choice of an appropriate reaction medium is of crucial
importance for a successful synthesis. Initially, the three-component
reaction of lawsone 1, p-nitrobenzaldehyde 2 and p-nitroaniline 3
was investigated as a simple model to establish the feasibility of
the strategy and optimize the reaction conditions (Scheme 2).
Experimental protocols were initially tested as described in pre-
vious report.12 The best results were obtained using a slightly mod-
ified procedure employing 10 mol % of excess of amine in an order
to increase the nucleophilicity of lawsone by deprotonation and
20 mol % of excess of aldehyde which helps to shift the equilibrium
towards the formation of the iminium ion.
Toluene (4 mL)
a
Reaction conditions: lawsone (1 mmol), p-nitrobenzaldehyde (1.2 mmol), p-
nitroaniline (1.1 mmol) and solvent, at room temperature.
b
The volume of solvent was varied to maintain the homogeneity of the reaction
medium.
reaction times and yields were evaluated. Initially, 10 mol % of
the catalyst was utilized as a standard. The results showed that
Brønsted–Lowry acids were more effective than Lewis acids, most
likely because they facilitate the formation of an electrophilic
iminium ion. In general, p-toluenesulfonic acid (entry 4, Table 2)
was the best catalyst for the multicomponent Mannich reaction.
To optimize the amount of catalyst, various trial reactions were
performed with 1, 10, 20 and 50 mol % p-toluenesulfonic acid as a
catalyst. Among them, 10 and 20 mol % of p-TsOH provided the
best results for the formation of products (Table 3).
Note that increasing the amount of catalyst did not result in an
increased yield of product and/or decreased reaction time (entry 4,
Initially, different solvents were screened in the model reaction,
and the chemical yields and reaction times were evaluated with
acetonitrile giving the best results (entry 3, Table 1).
Table 2
Model reaction and catalyst screeninga
Subsequently, a study was conducted with various Brønsted–
Lowry and Lewis acids to assess the effectiveness of these com-
pounds as catalysts for the model reaction (Table 2). Again, the
O
O
O
OH
NH2
O
OH
H
N
Catalyst
+
+
H
CH3CN, rt
O
O2N
NO2
NO2
3
4
1
2
NO2
O
O
O
O
O
OH
OH
CH3
S
N
H
HO
H
N
OH
Entry
Catalyst
—
Fe2(SO4)3ÁxH2O
AlCl3Á6H2O
I2
Time (h)
Yield (%)
O
1
2
3
4
5
6
6
2
0.75
1
0.75
2
60
66
84
90
94
98
NSC 672121
Atovaquone
Asterriquinone
Cl
O
O
O
O
O
H
OH
O
O
S
H3C
O
CH3
H
N
H3C
CF3CO2H
p-TsOH
CO2H
CH3
HO
N
H
H3C
Adociaquinone B
O
O
a
Lapachol
Reaction conditions: lawsone (1 mmol), p-nitrobenzaldehyde (1.2 mmol), p-
nitroaniline (1.1 mmol) and catalyst (10 mol %) in CH3CN (3 mL), at room
temperature.
Nakijiquinone
Figure 2. Quinones with biological activity.

R. G. Fiorot et al. / Tetrahedron Letters 55 (2014) 4373–4377
4375
Table 3
Table 3), which leads us to believe that the largest amount of the
catalyst is not immobilized by amine.
Model reaction and screening of amount of catalysta
To further extend the scope of this methodology, a one-pot, three
component Mannich reaction was performed under the same
conditions described previously using p-nitroaniline and the alicy-
clic secondary amine pyrrolidine with substituted aromatic
aldehydes containing electron-withdrawing group (nitro) or elec-
tron-donating groups (i.e., hydroxyl, methoxyl) and non-substituted
aromatic aldehydes (Table 4). Aliphatic aldehydes were also used,
although reflux conditions were required for these reactions (entries
11 and 12).
As expected, the reaction works best with aldehydes containing
electron-withdrawing by increasing the carbonyl electrophilicity
(entries 1 and 9). The reactions with salicylaldehyde also showed
good yields despite the hydroxyl group role—electrons donor
(entries 2 and 6). It occurs probably owing to the formation of
intramolecular hydrogen bond between the hydroxyl and carbonyl
O
O
O
OH
NH2
O
OH
H
p-TsOH
N
+
+
H
CH3CN, rt
O2N
NO2
O
NO2
3
4
1
2
NO2
Entry
Concentration
Catalyst
Time (h)
Yield (%)
1
2
3
4
1 mol %
p-TsOH
p-TsOH
p-TsOH
p-TsOH
0.85
0.75
0.5
90
98
98
97
10 mol %
20 mol %
50 mol %
0.5
a
Reaction conditions: lawsone (1 mmol), p-nitrobenzaldehyde (1.2 mmol), p-
nitroaniline (1.1 mmol) and p-TsOH (x mol %) in CH3CN (3 mL), at room
temperature.
Table 4
Scope of the multicomponent Mannich reaction
Entry
Aldehyde
Amine
Adduct
Time (h)
Yield (%)
Time (h)/yield (%) (classical method)a
O
O
O
OH
H
N
1
0.5
98
24/82
NO2
4
NO2
OH
H
N
2
3
4
6.0
10.0
8.0
73
95
90
20/69
24/93
24/90
O
O
NO2
OH
5
6
OH
H
N
O
O
NO2
O
H
OH
H
N
O
O
NO2
7
8
9
O
OH
H
H
N
H3CO
5
18.0
78
24/68
O
O
O
NO2
OCH3
OH
N
6
1.6
99
24/77
OH
(continued on next page)

4376
R. G. Fiorot et al. / Tetrahedron Letters 55 (2014) 4373–4377
Table 4 (continued)
Entry
Aldehyde
Amine
Adduct
Time (h)
Yield (%)
Time (h)/yield (%) (classical method)a
O
OH
N
7
4.0
89
24/32
O
O
10
11
O
H
OH
OH
N
N
8
6.0
85
24/38
O
O
9
1.2
94
24/46
O
O
12
NO2
OH
O
H
H3CO
N
10
48
55
96/44
O
13
OCH3
N
O2N
OH
OH
11
12
8.0 (reflux)
89
82
—
—
14
O
N
O2N
8.0 (reflux)
14
O
a
Classical method conditions: lawsone (1 mmol), aldehyde (1.2 mmol), amine (1.1 mmol) and ethanol (10 mL) as solvent, at room temperature.
oxygen in salicylaldehyde making it more electrophilic. The meth-
oxyl group in the para position of the aromatic ring decreases the
reactivity of the aldehyde carbonyl (entries 5 and 10). Surprisingly,
with aliphatic aldehydes, the expected Mannich adducts were not
obtained, but the same product was observed in both reactions
(entries 11 and 12).
catalyst, however; a reasonable possibility is shown in Scheme 3.
First, the catalyst protonates the carbonyl oxygen of the aldehyde
favoring the formation of the iminium ion which reacts with the
nucleophilic species, that may be the ion formed from deprotona-
tion of lawsone by the amine. Finally, the product is obtained after
tautomerism and the catalyst is regenerated.
This product was poorly soluble in commonly used NMR sol-
vents, possibly due to zwitterion form of the imine 14 (Fig. 3). It
was characterized via electrospray ionization coupled to Fourier
transform ion cyclotron resonance mass spectrometry (ESI(À)-FT-
ICR MS), showing an unambiguous molecular formula of
In conclusion, we describe the first use of p-toluenesulfonic acid
as an inexpensive and readily used catalyst for the multicompo-
nent Mannich reaction derived from lawsone. It has provided
excellent reaction times and within the reactions tested, the best
results were with aromatic aldehydes, provided Mannich bases
were in good and excellent yields.
C
16H10N2O4 and a ion [MÀH]À of m/z 293.0570.
The formation of this product likely occurs through nucleophilic
addition of the amine to the activated carbonyl of naphthoquinone
in the acidic medium. The molecular structure was confirmed by
ESI(À)-MS/MS experiments, which showed the losses of ÅOH
(293?276), NO (276?246) and HNO2 (293?246).
We have not established an exact mechanism for the formation
of the aminonaphthoquinones derived from lawsone using
Acknowledgments
The authors acknowledge the Conselho Nacional de Desenvolvi-
´
´
mento Cientifico e Tecnologico (CNPq), the Coordenadoria de
Aperfeiçoamento de Pessoal do Nível Superior (CAPES) and the

R. G. Fiorot et al. / Tetrahedron Letters 55 (2014) 4373–4377
4377
O2N
MOL files and InChiKeys of the most important compounds
described in this article.
O2N
O2N
N
O
NH
O
NH
O
OH
References and notes
O
O
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14
Exact Mass: 294,06
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Figure 3. Product obtained with aliphatic aldehydes.
O
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R1
R
O
H
O
OH
HA
R2NH2
H
+ A
R1
N
R2
O
R1
R
R2NH3 + A
R2NH2
Tautomerism
O
O
O
R2
H
H
N
H2O
N
R2
H
R1
Iminium ion
O
O
O
O
O
OH R2 NH2
Scheme 3. Proposed mechanism for catalytic Mannich reaction.
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Bioorg. Med. Chem. Lett. 2005, 15, 5324; (b) Tandon, V. K.; Yadav, D. B.;
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´
`
Fundação de Amparo a Pesquisa do Espirito Santo (FAPES) for their
financial support.
Supplementary data
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Supplementary data (materials, analytical methods, general
procedures and characterization of all synthesized compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.06.031. These data include