Facile synthesis of aminonaphthoquinone Mannich bases by noncatalytic multicomponent reaction

Article abstract of DOI:10.1080/00397911.2017.1371760

Mannich bases are formed in a noncatalytic multicomponent reaction, which is promoted by ultrasound irradiation. The procedure avoids the use of toxic solvents, catalyst, and purification, generating the desired compounds in excellent yields and short reaction times.

Full text of DOI:10.1080/00397911.2017.1371760

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Facile synthesis of aminonaphthoquinones
Mannich bases by non-catalytic multicomponent
reaction
Lluvia Itzel López-López, Sendar Daniel Nery-Flores, Aidé Sáenz-Galindo &
Denisse de Loera
To cite this article: Lluvia Itzel López-López, Sendar Daniel Nery-Flores, Aidé Sáenz-
Galindo & Denisse de Loera (2017): Facile synthesis of aminonaphthoquinones Mannich
bases by non-catalytic multicomponent reaction, Synthetic Communications, DOI:
10.1080/00397911.2017.1371760
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1371760
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Date: 10 September 2017, At: 00:05

Facile synthesis of aminonaphthoquinones Mannich bases by
non-catalytic multicomponent reaction
Lluvia Itzel López-López
School of Chemistry, Universidad Autónoma de Coahuila, Saltillo, Coahuila, MX
Sendar Daniel Nery-Flores
School of Chemistry, Universidad Autónoma de Coahuila, Saltillo, Coahuila, MX
Aidé Sáenz-Galindo
School of Chemistry. Universidad Autónoma de Coahuila, Saltillo, Coahuila, MX
Denisse de Loera
Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí, MX
ABSTRACT
Mannich bases are formed in a non-catalytic multicomponent reaction, which is promoted
by ultrasound irradiation. The procedure avoid the use of toxic solvents, catalyst and purification,
generating the desired compounds in excellent yields and short reaction times.
GRAPHICAL ABSTRACT
1

KEYWORDS: aminonaphthoquinone, green reaction, lawsone, Mannich bases, ultrasound
irradiation
Introduction
Naphthoquinones are important compounds that are widely distributed in different families
of plants, fungi and some animals.[1] Many naphthoquinones and synthetic analogues have
interesting biological activities like antibacterial, antifungal, antiviral, trypanocidal, antimalarial,
leishmanicidal, molluscicidal and insecticidal properties.
Also their anticancer activity has attracted research interest.[2] An important derivative of
1,4-naphthoquinone is 2-hydroxy-1,4-naphthoquinone or lawsone, commonly known as henna,
this has been used in cosmetics as hair dye, body paint and tattoo dye. The leaves are used as a
prophylactic against skin diseases,[3] another very interesting use is as ultraviolet filter in sunscreen
formation.[4] Moreover, lawsone is associate with antitumor, antibacterial and antifungal
activities.[5] Also, there is reported that amino substitution in 1,4-naphthoquinone increase the
biological activity.[6]
3-(Aminomethyl)-2-hydroxy-1,4-naphthoquinone known as Mannich base was first
synthesized in 1947 by Leffler and Hathaway by the condensation reaction of lawsone, a non-
enolizable aldehyde and a primary or secondary amine. They also described their antimalarial
2

activity.[7a] Vaughan and coworkers reported the reaction between lawsone, several amines with
formaldehyde and acetaldehyde, they show moderat to low yields.[7b] Mannich reaction is a classic
method for the preparation of α-amino carbonyl compounds and a principal alternative to generate
C-C bonds.
There is reported improvements in the three component reaction to prepare Mannich
Bases.[8] Reactions carried out in Brönsted acids,[9] Lewis acids,[10] Lewis bases,[11] or organic
molecules[12] as catalysts have shown moderate yields but long reaction times, also it is required
toxic reagents or catalysts that are atmosphere sensitive. Recently, Allochio Filho and coworkers
presented the synthesis of aminonaphthoquinones derived from lawsone via a multicomponent
Mannich reaction in aqueous media utilizing a Brønsted acid-surfactant catalyst (BASC) at room
temperature, in this case the yields were from moderate to good but the reaction times were
between 12-216hours .[13a] Mannich reaction was used in the synthesis of 3,4-dihydro-2H-
naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives using ionic liquid, [13b] and also in the synthesis
of naphthoquinone dendrimers as potential antimalarial drugs.[13c]
Multicomponent reactions have received considerable interest since they show good atom
economy, they are highly convergent, and require minimal time and effort to obtain complex
molecules.[14] Ultrasound irradiation is considered an alternative source of energy and has been
established as a versatile technique in synthetic chemistry. The phenomenon observed is known as
“acoustic cavitation”, and generates high temperatures and pressures in localized zones of the
liquid creating a rate acceleration in many organic reactions.[15]
We present the synthesis of Mannich Bases via a multicomponent reaction (three-
component) ultrasound assisted between lawsone (1), benzaldehyde (2) and primary amines (3a-
e), Scheme 1. Initial experiments carried out using 2-hydroxy-1,4-naphthoquinone (1),
3

benzaldehyde (2) and 3-chloroaniline (3a) to optimize the experimental conditions. The results are
summarized in Table 1. The methodology presented is easy, atom-economical, fast and
environmentally benign.
Results and Discussion
The expected Mannich base 4a was obtained in good yields using 15, 30 and 60minutes of
irradiation time (Table 1, entries 1-3). The results revealed that irradiation time higher than
15minutes has not significant effect, therefore, subsequent experiments were performed at
15minutes of irradiation considering the importance of minimized energy requirements in order to
present an economic and environmentally friendly reaction. We also tested different solvents
(Table 1, entries 4-6), these were selected based on their health, safety and environment criteria.[16]
The best result was obtained with ethanol, 90%, (Table 1, entry 1), methanol slightly decreased
the yield, 80% (entry 4), finally water and water:ethanol mixture yielded the expected product in
43% and 40%, respectively (entries 5,6).
As mentioned above, Brönsted acids, Lewis acids and bases, or catalysts improved the
yields and reaction times.[10–12] Therefore, we also investigated the effect of CeCl3•7H2O. Table 2
shows the yield of 4a with different amounts of catalyst (entries 1-4). Contrary to the results
reported in literature,[10b,c] the reaction efficiency decreased. In fact, the amount of the
corresponding compound was 81% with 0.1 mmol of catalyst, 79% with 0.2 mmol and 65% with
0.3 mmol. In order to corroborate this fact, we performed the same experiments with 2,4-
difluoroaniline 3d, in this case the Mannich base 4d was obtained in 28, 26 and 13%, respectively
(Table 2, entries 6-8). The reduction is attributed to the formation of two additional products, one
of them in substantial amount. According to lawsone reactivity, this secondary product
4

corresponds to Michael addition of aniline to 2-hydroxy-1,4-naphthoquinone. To confirm this
theory, a reaction between 2-hydroxy-1,4-naphthoquinone (1) and 2,4-difluoroaniline (3d) was
carried out. The compounds obtained in both reactions (with and without benzaldehyde) had the
same melting point, color and retention factor (Rf) indicating that the reaction mechanism with
CeCl3•7H2O corresponds to Michael addition, generating 2-hydroxy-3-(2,4-difluoroanilino)-1,4-
naphthoquinone.
Table 3 shows the results of the synthesis of five Mannich bases under optimized
conditions, also the results of reaction under stirring at room temperature were presented. In both
cases, the corresponding Mannich bases, 4a-e, were obtained in good yields, above 80%, but the
reaction time is considerable less using ultrasonic irradiation, from 15hours to 15minutes .
A possible mechanisms for the formation of 4a is presented in Scheme 2. First, nucleophilic
attack of 3-chloroaniline (3a) to the electrophilic carbon in benzaldehyde (2) with the subsequent
dehydration generated the imine intermediate (1b). Then, an excess of amine promoted the lawsone
enol form (1a) which attacked the imine 1b to yield the desired product 4a.
As mentioned, the presence of CeCl3•7H2O facilitated the Michael reaction, we assume
that the catalyst coordinated with the lawsone oxygen activating the C-2 position in the 2-hydroxy-
1,4-naphthoquinone, where the aniline attacked to generate the secondary product.
Conclusion
To conclude, we have developed a non-catalytic effective procedure to prepare Mannich
bases lawsone derivatives using one-pot synthesis promoted by ultrasound irradiation with short
reaction times, high yields, and cleaner products by avoiding by-products formation. As a matter
of fact, the products obtained were recovered by filtration without further purifications. Mannich
5

bases lawsone derivatives are important intermediates in the synthesis of compounds with
pharmacological properties, therefore this procedure represents a potential technique for synthesis
of compounds with important applications.
Experimental
General experimental
All chemicals were obtained from commercial suppliers and used without further
purification. Melting points were determined using a Fisher-Scientific Melting Point Tester and
were no corrected. Silica gel (Kieselgel 60 F254, Merck) plates were used for thin layer
1
chromatography (TLC). H NMR spectra were recorded on Varian Mercury 400 spectrometer at
400MHzand 13C spectra were recorded at 100MHz using DMSO-d6 and CDCl3 as solvent.
Chemical shifts are reported in parts per million (ppm, δ), relative to the internal standard of
tetramethylsilane (TMS). Mass spectra were performed on a Jeol JMS-100D mass spectrometer
equipped with electrospray ionization (ESI) interface and ion trap analyzer. The ultrasound
assisted reactions were carried out in a Branson 5510 bath cleaner (45 KHz, 135W ).
General synthesis
To a suspension of lawsone (2.5 mmol) and primary amine (2.75 mmol, 3a-e) in ethanol
(7.5mL ) at room temperature, benzaldehyde (3 mmol) was added. The mixture was placed in the
center of an ultrasound cleaner bath at room temperature. The progress of the reaction was
monitored by TLC. After reaction completion, the reaction mixture was cooled in an ice-bath and
the solid formed was filtered, washed with cold ethanol and dried under vacuum.
Characterization data for compounds 4a
6

2-[(3-chlorophenylamino)phenylmethyl]-3-hydroxy-1,4-naphthoquinone (4a).
Light green powder, Mp, 136°C. 1H NMR (400MHz, CDCl3): δ(ppm) 10.02 (s, 1H), 8.52
(s, 1H), 8.07 (d, 2H), 7.75 (t, 1H), 7.68 (t, 1H), 7.51 (d, 2H), 7.33 (t, 2H), 7.26 (t, 1H), 7.05 (t, 1H),
6.74 (s, 1H), 6.68 (d, 1H), 6.62 (d, 1H), 6.13 (s, 1H); 13C NMR (100MHz, CDCl3): δ(ppm) 135.3,
133.3, 130.3, 128.7, 127.6, 127.0, 126.6, 126.4, 118.3, 113.7, 111.9, 52.7. IR (ATR): 3441, 3319,
1660, 1599, 1497, 1351, 1274, 1009, 704cm -1. ESI-MS: m/z [M]+ calcd for C23H16ClNO3:
389.0819; found: 389.0813.
Acknowledgment
This work was supported by Council National of Science and Technology (SEP-CB-2011-
01) under grant agreement No. 0167668. The author want to thank BUAP for performed products
characterization.
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9

Table 1. Synthesis of 4a under various conditionsa.
Entry
Time (min)
Solvent
EtOH
Yield (%)
1
2
3
4
5
6
15
30
60
15
15
15
90
89
91
80
43
40
EtOH
EtOH
MeOH
H2O
H2O:EtOH (1:1)
aLawsone (2.5 mmol), benzaldehyde (3 mmol) and 3-chloroaniline (2.75 mmol).
10

Table 2. Effect of CeCl3•7H2O amount in synthesis of Mannich basesa.
Entry
Product
4a
CeCl3•7H2O
Yield (%)
94
1
2
3
4
5
6
7
8
0
4a
0.1
0.2
0.3
0
81b
4a
79b
4a
65b
4d
80
4d
0.1
0.2
0.3
28b
4d
26b
4d
13b
aLawsone (2.5 mmol), benzaldehyde (3 mmol) and aniline (2.75 mmol).
bThe isolated product presented two additional products.
11

Table 3. Mannich reaction of lawsone, primary amine and benzaldehyde.a
Entry
Primary amine
3-Chloroaniline
4-Nitroaniline
Product
4a
Yield (%)b
Yield (%)c
1
2
3
4
5
93
98
94
66
83
94
90
91
80
90
4b
2,4-Dichloroaniline
2,4-Difluoroaniline
Hexylamine
4c
4d
4e
aLawsone (2.5 mmol), benzaldehyde (3 mmol) and primary amine (2.75 mmol).
bThe reagents were mixed and left stirring at room temperature for 15 hours.
cThe reagents were mixed and irradiated under ultrasonic irradiation for 15 minutes.
12

Scheme 1. Synthesis of Mannich bases derived from lawsone under ultrasonic irradiation.
13

Scheme 2. Proposed reaction mechanism of 4a formation.
14