Molecular diversity from the three-component reaction of 2-hydroxy-1,4-naphthaquinone, aldehydes and 6-aminouracils: a reaction condition dependent MCR

Article abstract of DOI:10.1039/C6RA18828A

The three-component reaction of 2-hydroxy-1,4-naphthaquinone, aldehydes, and 6-aminouracil derivatives in acetic acid/water (1?:?1; v/v) under microwave heating conditions provides 1,4-dihydropyridines fused with naphthaquinone and pyrimidines. On the oth

Full text of DOI:10.1039/C6RA18828A

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Molecular diversity from the three-component
reaction of 2-hydroxy-1,4-naphthaquinone,
aldehydes and 6-aminouracils: a reaction condition
dependent MCR†
Cite this: RSC Adv., 2017, 7, 3928
a
a
a
b
*
*
Ruchi Bharti, Pooja Kumari, Tasneem Parvin and Lokman H. Choudhury
The three-component reaction of 2-hydroxy-1,4-naphthaquinone, aldehydes, and 6-aminouracil derivatives
in acetic acid/water (1 : 1; v/v) under microwave heating conditions provides 1,4-dihydropyridines fused with
naphthaquinone and pyrimidines. On the other hand the same reaction combinations under conventional
reflux conditions provide acyclic trisubstituted methane derivatives. Using these tuneable reaction
conditions a series of polycyclic fused N-heterocycles has been synthesized. The notable features of this
methodology are a simple metal-free one-pot operation, easy purification process, use of the green
solvent water, short reaction time and good to moderate yields of the products.
Received 25th July 2016
Accepted 12th December 2016
DOI: 10.1039/c6ra18828a
www.rsc.org/advances
Polycyclic fused N-heterocycles have attracted much attention
due to their presence in biologically active natural products and
Introduction
pharmaceuticals. They display a wide range of biological activ-
ities such as antifungal, antibacterial, antineoplastic, anti-
cancer, antiplasmodial, and as DNA intercalators.7 The
presence of several functional groups in one molecule oen
proves useful to nd better bioactivities of compounds. Further,
literature survey shows that fused polycyclic N-heterocycles
containing naphthaquinone,8–10 1,4-dihydro pyridine11–13 and
pyrimidine14 moieties are important in discovering new bioac-
tive compounds due to their fascinating molecular structure
and remarkable pharmacological efficiency. This class of
building blocks are useful for treating Alzheimer's disease15 and
also exhibit anti-tumor,16 antimicrobial,17 anti-diarrhea,18 and
One-pot multicomponent reactions (MCRs) have emerged as an
efficient tool for benign synthesis of functionalized heterocycles
by virtue of their convergence, productivity, facile execution,
and generation of highly diverse and complex products from
easily available starting materials in a single operation.1 MCRs
are very useful to access “privileged medicinal scaffolds”,
especially, for synthesizing various N-heterocyclic compounds
which are key constituents of a wide range of both natural and
synthetic bioactive compounds.2,3 Microwave assisted multi-
component reactions have drawn remarkable attention from
organic and medicinal chemists considering their green
features. MW irradiation provides enhanced reaction rates,
higher yields of products, better selectivity, rapid optimization
of reactions and several ecofriendly advantages.4 Further, in
comparison with organic solvents, water is a non-toxic, non-
corrosive, non-explosive and is readily available solvent. These
properties along with the network of hydrogen bonds, large
surface tension, high polarity and high specic heat capacity
make it both economical and environmentally friendly and thus
suitable as a green solvent.5,6 According to the current synthetic
requirements and from green perspective, environmentally
benign multicomponent procedures employing microwave
methodology in aqueous medium are particularly welcome.
aDepartment of Chemistry, National Institute of Technology Patna, Ashok Rajpath,
Patna-800 005, Bihar, India. E-mail: tasneem@nitp.ac.in
bDepartment of Chemistry, Indian Institute of Technology Patna, Bihta, Patna-801103,
Bihar, India. E-mail: lokman@iitp.ac.in
† Electronic supplementary information (ESI) available: General experimental
procedure, characterization data, with copies of 1H, 13C NMR spectrum. See
DOI: 10.1039/c6ra18828a
Fig. 1 Examples of pharmaceutically important fused polycyclic N-
heterocycles and their activities.
3928 | RSC Adv., 2017, 7, 3928–3933
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using multicomponent reaction.20 Recently various research
groups have explored 6-amino uracil in multicomponent reac-
tions to construct fused heterocycles.21
Considering the importance of fused polycyclic N-
heterocycles having naphthaquinone, 1,4-DHP and pyrimidine
moieties in pharmaceutical and chemical domains, and also as
a part of our continuous effort on the synthesis of highly
functionalized or fused heterocycles,22–24 we turned our atten-
tion to design a thee component reaction of 2-hydroxy-1,4-
naphthaquinone (1), 6-aminouracils (2) and aldehydes (3). In
acetic acid/water (1 : 1) under reux conditions we ended with
acyclic products 5 (Scheme 1). Interestingly, when we carried
out the same reaction under microwaves in acetic acid/water
Scheme 1 Formation of 4 and 5 in different reaction conditions from
the three component reactions.
(1 : 1), we ended with fused polycyclic N-heterocycles
4
(Scheme 1). It consists of three important bioactive moieties
naphthaquinone, 1,4-dihydropyridine and pyrimidine (Fig. 2).
Results and discussion
For the preliminary investigation, reaction of 2-hydroxy-
1,4-naphthaquinone 1, 1,3-dimethyl-6-aminouracil 2a and 4-
methyl benzaldehyde 3c was chosen as model reaction. In the
presence of acetic acid under the reux conditions, this
combination provided 75% of acyclic product 5ac within 5 h
(Table 1, entry 1) and we did not get our desired three compo-
nent cyclic product 4ac under this reaction conditions. Next, we
attempted to get the cyclized product by varying various
parameters of the reaction, such as using microwave heating,
solvent etc. Interestingly, the same model reaction provided
77% yield of the corresponding fused polycyclic N-heterocyclic
product 4ac and 12% of acyclic product 5ac, aer microwave
heating at 130 ꢀC for 15 minutes in acetic acid medium (Table 1,
entry 2). The product 4ac was fully characterized by recording
Fig. 2 Product having three important bioactive moieties.
anti-cancer activities.19 Some of the pharmacologically active
fused polycyclic N-heterocycles are shown in Fig. 1.
6-Aminouracil is considered as a very popular and useful
starting material for the synthesis of heterocyclic scaffolds
Table 1 Optimization of reaction conditionsa
Entry
Solvent
Reaction conditions
Yieldb (%) 4ac/5ac
Time (h/min)
1
2
3
4
5
6
7
8
AcOH
AcOH
H2O
EtOH
DMSO
PEG-400
AcOH/H2O (1 : 1)
AcOH/EtOH (1 : 1)
AcOH/H2O (1 : 1)
AcOH/DMF (1 : 1)
AcOH/CH3CN (1 : 1)
AcOH/DMSO (1 : 1)
Reux
MW
MW
MW
MW
MW
Reux
MW
MW
MW
MW
MW
0/75
5 h
77/12
66/15
51/12
0/53
0/72
0/80
76/15
90/8
56/21
68/14
48/40
15 min
15 min
15 min
15 min
15 min
5 h
15 min
15 min
15 min
15 min
15 min
9
10
11
12
a
Reactions were carried out in 1.0 mmol scale with 1 : 1 : 1 ratio of 2-hydroxy-1,4-naphthaquinone, 1,3-dimethyl-6-aminouracil and 4-methyl
benzaldehyde in 2 ml solvent. b Isolated yields.
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Table 3 Scope of the reactiona
IR, 1H & 13C NMR as well as HRMS. Encouraged by this positive
result, the same set of reaction was performed in various
solvents under microwave heating and the results are summa-
rized in Table 1 (entries 3–6). Interestingly, it has been observed
that when the reaction was performed in the presence of protic
solvents like AcOH, H2O, and EtOH it gives cyclic product 4ac as
major and acyclic product 5ac as minor product (Table 1 entries
2–4). But when the reaction was performed in DMSO and PEG-
400, only acyclic product 5ac was observed (Table 1, entries 5
and 6). To further investigate, we also performed the same
model reaction using mixed solvent like acetic acid and other
solvent (1 : 1) under reux as well as microwave reaction
conditions (Table 1, entries 7–12). Among them, acetic acid/
water (1 : 1) under microwave heating was found as optimum
reaction conditions in terms of yield obtained (Table 1, entry 9).
In order to explore the scope of this multicomponent reac-
tion, a wide variety of aldehydes 3a–r were reacted with 2-
hydroxy-1,4-naphthaquinone 1 and aminouracil derivatives 2a–
b under the optimized reaction conditions and the results are
Entry
R
R1
% yieldb of 4
% yieldb of 6
1
2
CH3
CH3
4-CNC6H4
3-NO2C6H4
4ao
4ap
38
35
6ao
6ap
52
58
a
Reactions were carried out with 1 : 1 : 1 ratio of 2-hydroxy-1,4-
1,3-dimethyl-6-aminouracil and 4-
naphthaquinone,
methylbenzaldehyde in acetic acid/water (1 : 1) under microwave
b
irradiation. Isolated yields.
summarized in Table 2. It is notable that the characteristics of
2a–b and 3a–r had an important inuence on the nal products.
In most of the cases when 2a was employed, cyclic product 4 was
obtained as major and acyclic product 5 as minor product
(Table 2, entries 1–7 and 9). However, in the cases of 2-chlor-
obenzaldehyde 3h, naphthaldehyde 3j and 2-methox-
ybenzaldehyde 3k, we obtained exclusively cyclic product and
Table 2 Scope of the reactiona
% yieldb
of 4
% yieldb
Entry
R
R1
of 5c
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
C6H5
4-ClC6H4
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
79
87
90
85
82
64
71
90
78
85
92
89
91
87
89
87
92
96
93
87
87
78
—
—
5aa
5ab
5ac
5ad
5ae
5af
5ag
5ah
5ai
13
10
8
4-CH3C6H4
4-OCH3C6H4
4-CH(CH3)2C6H4
4-NO2C6H4
4-FC6H4
2-ClC6H4
3-BrC6H4
Naphthyl
2-OCH3C6H4
C6H5
4-OCH3C6H4
4-CH(CH3)2C6H4
4-FC6H4
2-ClC6H4
3-BrC6H4
2-OCH3C6H4
2-CH3C6H4
2,6-DiCH3C6H3
4-BrC6H4
4-CNC6H4
Cyclohexyl
Butyl
10
12
32
25
—
18
—
—
—
—
—
—
—
—
—
—
—
—
—
81
79
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4aj
5aj
4ak
4ba
4bd
4be
4bg
4bh
4bi
5ak
5ba
5bd
5be
5bg
5bh
5bi
4bk
4bl
5bk
5bl
4bm
4bn
4bo
4aq
4ar
5am
5bn
5bo
5aq
5ar
H
H
CH3
CH3
a
Reactions were carried out in 1.0 mmol scale with 1 : 1 : 1 ratio of 2-
hydroxy-1,4-naphthaquinone, 1,3-dimethyl-6-aminouracil and 4-
methylbenzaldehyde in acetic acid/water (1 : 1) in microwave.
Fig. 3 Comparison of 1H NMR spectra of cyclic product 4ac with
acyclic product 5ac.
b
c
Isolated yields. For full characterization of compounds 5, please
see ref. 22.
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no acyclic product (Table 2, entries 8, 10 and 11) was observed.
Further, when 6-aminouracil 2b was tested with 1 and different
substituted aldehydes 3(a, d–e, g–i, k–o) only cyclic products
were observed (Table 2, entries 12–22). Next we examined some
aliphatic aldehydes such as cyclohexyl carboxaldehyde 3q and
butyraldehyde 3r. Unfortunately, they provided acyclic product
only (Table 2, entries 23 and 24). However, when 4-cyano-
benzaldehyde 3o and 3-nitrobenzaldehyde 3p were used, we
obtained 6ao and 6ap along with 4ao and 4ap (Table 3, entries 1
and 2) respectively.
Scheme 3 Synthesis of cyclic product from the acyclic one.
1
All the products were fully characterized by IR, H NMR, 13C
NMR spectroscopy as well as HRMS. The formation of 4 and 5 were
ascertained from NMR spectroscopy with compound 4ac and 5ac
(Fig. 3). As a representative case, 1H NMR of 4ac was interpreted by
the presence of a singlet at 8.82 for –NH proton, 8.08–7.00 ppm for
1
eight Ar-H protons, and singlet at 5.22 for CH proton. While, H
NMR of 5ac was characterized by the presence of a singlet at 13.28
for –OH proton, 8.26–7.77 and 7.15–6.90 ppm for eight Ar-H
proton and two singlets at 7.19 and 5.79 for –NH2 and –CH
protons respectively. From this it is clear that the product 4ac is
the fused polycyclic N-heterocycle whereas the acyclic product is
5ac where free –NH2 and –OH groups are present.
The formation of product 4, can be explained by the
proposed mechanism, as shown in Scheme 2. The reaction is
initiated by a acetic acid assisted aldol condensation to provide
A which transforms to B aer elimination of water molecule.
Then B reacts with 6-aminouracil derivatives 2a–b in a Michael-
type fashion and gave C which undergoes intramolecular
condensation followed by tautomerization to give the corre-
sponding product (4).
Next, we attempted to convert acyclic product which we ob-
tained under reux conditions to the corresponding cyclic
products. For that we have treated the acyclic product 5ac in
acetic acid/water (1 : 1) under MW heating for 15 min and the
corresponding cyclic product 4ac was obtained in 78% yield
(Scheme 3).
Finally, we explored cinnamaldehyde an a,b-unsaturated
aldehyde in this three component reaction under the similar
reaction conditions. To our surprise, this aldehyde did not
provide expected acyclic product 5as or cyclic product 4as,
instead of these a novel unexpected cyclic product 7as was
obtained as shown in Scheme 4.
Scheme 4 Synthesis of unexpected product 7as from the reaction of
cinnamaldehyde, 2-hydroxy-1,4-naphthaquinone and 2a.
Conclusions
In conclusion, we have demonstrated the effects of reaction
conditions on the formation of two types of products from the
three-component reaction of 2-hydroxy-1,4-naphthaquinone,
aldehydes and 6-aminouracils. This method is a green tool for
the synthesis of fused polycyclic N-heterocycles in acetic acid/
water under microwave heating. The main advantages of this
method are (i) easy purication process of the products avoiding
column chromatographic purication, (ii) high atom economy of
the reaction (iii) use of water as solvent, (iv) short reaction time,
(v) good yields of the products and (vi) environmentally benign
procedures. Considering the presence of naphthaquinone and
pyrimidine moiety fused with 1,4-DHPs, it is expected that these
products will exhibit promising bioactivities.
Acknowledgements
We are grateful to NIT Patna and IIT Patna for providing general
research facilities to carryout this work. T. P. is thankful to
SERB-DST, India for nancial support with Sanction No. EMR/
2016/000960. The authors are also thankful to SAIF-Panjab
University and SAIF-IIT Patna for providing the analytical
facilities for characterization of products.
Notes and references
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