Diversity oriented synthesis of tri-substituted methane containing aminouracil and hydroxynaphthoquinone/hydroxycoumarin moiety using organocatalysed multicomponent reactions in aqueous medium

Article abstract of DOI:10.1039/c5ra13093j

Synthesis of a series of tri-substituted methane derivatives has been reported via a one-pot multicomponent reaction of aldehyde, 1,3-dimethyl-6-aminouracil and 2-hydroxy-1,4-naphthoquinone/4-hydroxycoumarin using a bifunctional thiourea-based organocatal

Full text of DOI:10.1039/c5ra13093j

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Diversity oriented synthesis of tri-substituted
methane containing aminouracil and
hydroxynaphthoquinone/hydroxycoumarin moiety
using organocatalysed multicomponent reactions
in aqueous medium†
Cite this: RSC Adv., 2015, 5, 66833
*
Ruchi Bharti and Tasneem Parvin
Synthesis of
a series of tri-substituted methane derivatives has been reported via a one-pot
Received 5th July 2015
Accepted 17th July 2015
multicomponent reaction of aldehyde, 1,3-dimethyl-6-aminouracil and 2-hydroxy-1,4-naphthoquinone/
4-hydroxycoumarin using a bifunctional thiourea-based organocatalyst in aqueous medium. Use of the
organocatalyst, and water as a solvent, without the need for column chromatographic purification, are
the notable features of this methodology.
DOI: 10.1039/c5ra13093j
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than two components react in one pot, have gained considerable
attention in recent times. Similarly organocatalysis16 imparts
Introduction
Tri-substituted methanes (TRSMs)1 are an important class of
molecules, with a wide range of pharmacological and biological
activities such as anti-cancer,2 antiproliferative,3 antitubercular4
etc. They are also used as molecular chemosensors5 and for the
generation of dendrimers.6 Substituted methane derivatives with
substituents such as aminouracil, hydroxynaphthoquinone/
hydroxycoumarin are considered as important bioactive mole-
cules. Some representative examples of tri-substituted methanes
with anticoagulant,7 antioxidant,8 antibacterial,9 antimicrobial10
and antibiolm10 activities are shown in Fig. 1.
Considering the importance of tri-substituted methanes,
Karami et al. have recently reported a three component reaction
of aryl aldehydes, 4-hydroxycoumarin and 3-methyl-1-phenyl-2-
pyrazolin-5-one using ZnO nanoparticles for the green synthesis
of tri-substituted methane derivatives.11 Panda et al. have also
reported the synthesis of tri-substituted methanes with aryl and
heteroaryl rings.12 Similarly, Atmakur et al.10 reported the
regioselective synthesis of highly functionalized 3-benzylpyr-
imidino chromen-2-ones in a one pot three component reaction
in acetic acid and determined their anti-microbial and anti-
biolm activities. Thus a plethora of methods is present in
the literature for the synthesis of tri-substituted methane
derivatives.13 From the green chemistry point of view, the design
of methodology with a pot, atom and step economic approach
has remained one of the prime goals in organic synthesis.14 In
this direction, multicomponent reactions (MCRs),15 where more
environmental friendliness in organic synthesis due to its
inherent low toxicity, metal free and simple reaction conditions.
Thus, employing organocatalysis in MCRs17 makes the process
greener. In continuation of our work18 on MCRs, we wanted to
design an organocatalyzed MCR for the synthesis of some struc-
turally divergent tri-substituted methanes with some bioactive
moieties such as aminouracil and hydroxynaphthoquinone/
hydroxycoumarin as substituents. Among the organocatalysts,
bifunctional thiourea-based organocatalysts19 are popular in
organic synthesis due to their activation of electrophiles by
double-hydrogen-bonding interactions with a thiourea moiety, as
well as the activation of nucleophiles by the other part (basic
moiety). In this paper we have reported a three component
Department of Chemistry, National Institute of Technology Patna, Ashok Rajpath,
Patna-800 005, India. E-mail: tasneem@nitp.ac.in
† Electronic supplementary information (ESI) available: 1H NMR and 13C NMR
Fig. 1 Biologically active tri-substituted methane derivatives con-
taining aminouracil and the hydroxynaphthoquinone/hydrox-
ycoumarin moiety.
spectra for all reactions products are available. See DOI: 10.1039/c5ra13093j
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ethanol under reux conditions.20 In continuation of our work
when we carried out a reaction of 4-chlorobenzaldehyde 1c, 1,3-
dimethyl-6-aminouracil 2 and 2-hydroxy-1,4-naphthoquinone 3
in H2O without any catalyst under reux conditions, we ended
with an acyclic product i.e., tri-substituted methane derivatives
instead of the cyclic product. The yield of the reaction was only
33% aer 6 h (Table 1, entry 1). Our next endeavour was to
enhance the yield of the reaction by employing various catalysts.
For this purpose, various catalysts were tested. We achieved a
slight improvement in the yield of the product, but the results
were still not very satisfactory (Table 1, entries 2–6). Interest-
ingly, when we performed the same reaction in the presence of
our newly synthesized thiourea-based organocatalyst I (Table 1,
entry 7), the maximum yield was obtained. It is noteworthy to
mention that a mixture of Et3N and thiourea (20 + 20) mol%
provided lower yields as compared to organocatalyst I (Table 1,
entry 8).
Scheme 1 Synthesis of tri-substituted methane derivatives.
Scheme 2 Synthesis of bifunctional thiourea-based organocatalyst I.
Table 1 Screening of catalysts
Next, we performed a screening of various solvents such as
H2O, EtOH, MeCN, THF, DMSO and toluene (Table 2, entries 1–
6) to see the effect of solvents on the reaction. The results of
Table 2 revealed that water was the best solvent for the reaction
in terms of yield and reaction time.
With the optimized reaction conditions, we then explored
the generality of the method by using various aldehydes (both
aromatic and aliphatic) with 2-hydroxy-1,4-naphthoquinone
and 1,3-dimethyl-6-aminouracil. The results are summed up
in Table 3. Aromatic aldehydes containing various substituents
like 4-Me, 4-Cl, 4-NO2, 4-OMe, 4-F, 4-Br, 4-CH(Me)2, 3-Br, 3-NO2
and aliphatic aldehydes like cyclohexyl aldehyde, butyraldehyde
underwent smooth reactions to provide the corresponding tri-
substituted methane derivatives (4a–4l) in good to moderate
yields. Next we tried a reaction with phenylacetaldehyde.
However, in this case the reaction provided an inseparable
mixture of products. It is quite clear from Table 3 that neither
the nature nor the positions of the substituents on the aromatic
ring in the aromatic aldehydes alter the yield of reaction to any
signicant extent. However, aliphatic aldehydes provide lower
yields as compared to aromatic one, which may be due to the
reduced stability as well as the tendency of those aldehydes to
exist in enol form.
Entries
Catalyst
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
—
—
H2O
AcOH
H2O
H2O
H2O
H2O
H2O
H2O
6
4
7
6
8
5
3
6
33
60
40
58
38
65
85
68
L-Proline
Thiourea
Et3N
DABCO
I
Et3N + thiourea
a
Isolated yield.
reaction of aldehyde, 1,3-dimethyl-6-aminouracil and 2-hydroxy-
1,4-naphthoquinone/4-hydroxycoumarin in aqueous medium in
the presence of a bifunctional thiourea-based organocatalyst for
the synthesis of tri-substituted methane derivatives (Scheme 1).
Aer the successful synthesis of tri-substituted methane
derivatives containing hydroxynaphthoquinone, aminouracil
and aromatic/aliphatic rings, we carried out a three component
reaction of 4-hydroxycoumarin, aldehyde and 1,3-dimethyl-6-
aminouracil under similar reaction conditions and we
obtained the corresponding tri-substituted methane derivatives
(Scheme 3).
Result and discussion
Considering the popularity, as well as the virtues of bifunctional
Looking at the molecular skeleton with pyrimidine and
thiourea-based organocatalysts in organic synthesis, we initially coumarin fragments in the tri-substituted methane derivatives,
synthesized organocatalyst I with a thiourea moiety and two as well as their biological activity, the scope of the reaction was
basic sites using a two component reaction of 2-piperidinoethyl tested with different substituted aldehydes and the results are
isothiocyanate and 4-amino-1-benzyl piperidine, as shown in presented in Table 4 (6a–f).
Scheme 2.
All the products were characterized by IR, 1H NMR, 13C NMR
Recently we have reported a L-proline catalyzed three spectroscopy and elemental analysis. To remove the ambiguity
component reaction of 2-hydroxy-1,4-naphthoquinone, alde- in structure further, a D2O exchange experiment was performed
hydes, and aminopyrazoles, which gives a cyclised product, 2H- with compound 4c. The labile protons of –NH2 and –OH van-
benzo[g]pyrazolo[3,4-b]quinoline-5,10(4H,11H)-diones,
in ished in the D2O exchanged 1H NMR spectra of 4c (Fig. 2). From
66834 | RSC Adv., 2015, 5, 66833–66839
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Table 2 Effects of solvents
synthesized compounds were ascertained by thin layer chro-
matography on silica gel GF 254 in ethyl acetate using iodine
vapour as the detecting agent. Melting points were determined
by the melting point apparatus using a capillary tube method.
IR spectra were recorded on a Shimadzu FTIR spectrophotom-
eter in KBr pellets. 1H NMR and 13C NMR spectra were recorded
either in CDCl3 or in DMSO-d6, and were expressed in parts per
million (d, ppm) downeld using Me4Si as the internal standard
on a Bruker Avance II 400 MHz spectrophotometer. Elemental
analyses were carried out on a Perkin-Elmer 2400 automatic
carbon, hydrogen, nitrogen analyzer.
Entries
Catalyst
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
I
I
I
I
I
I
H2O
3
5
7
12
8
6
85
75
72
34
<30
58
EtOH
MeCN
THF
DMSO
Toluene
Typical experimental procedure for the synthesis of
bifunctional thiourea based organocatalyst I
First, 4-amino-1-benzyl piperidine (0.5 mmol) was dissolved in 2
ml dichloromethane and allowed to cool at 0 ꢀC. Then 2-
piperidinoethyl isothiocyanate (0.5 mmol) was added into the
reaction mixture and stirred at room temperature until
completion of the reaction, as checked by TLC. The reaction
mixture was cooled, and the solid was ltered off and washed
with ethanol to afford the desired product.
a
Isolated yield.
this it was conrmed that the product was not cyclised and free
–NH2 and –OH groups were present in the tri-substituted
methane derivatives.
1-(1-Benzylpiperidin-4-yl)-3-(2-(piperidin-1-yl)ethyl)thiourea (I).
White powdery solid; mp ¼ 240–242 ꢀC; IR (KBr): 3273, 3151,
A plausible mechanism for the formation of tri-substituted
methane derivatives has been proposed in Scheme 4. Similar
to literature reports21 we believe that aldehyde initially reacts
with 3 or 5 via aldol condensation followed by dehydration to
give intermediate B. Then the third component undergoes
Michael addition followed by tautomerization to provide the
corresponding tri-substituted methane derivatives 4 or 6. We
believe our synthesized thiourea-based organocatalyst I plays a
dual role in this reaction. The basic functionalities present in
this organocatalyst activates nucleophiles and the thiourea
moiety activates the C]O group by a double hydrogen bonding
interaction.
1
3054, 2929, 1574, 1495, 1240, 961, 860, 747 cmꢁ1; H NMR (400
MHz, CDCl3): 7.33–7.22 (m, 5H), 6.72 (brs, 1H), 4.02 (brs, 1H), 3.51
(s, 2H), 3.45–3.38 (m, 2H), 2.88–2.85 (m, 2H), 2.48–2.42 (m, 7H),
2.15–2.09 (m, 2H), 2.05–2.02 (m, 2H), 1.59–1.51 (m, 6H), 1.48–1.47
(m, 2H) ppm; 13C (100 MHz, CDCl3): 181.1, 138.3, 129.3, 128.4,
127.9, 62.9, 54.5, 52.4, 41.8, 32.2, 30.9, 25.8, 24.1 ppm; anal. calcd
for C20H32N4S (360.56): C, 66.62; H, 8.95; N, 15.54; found: C, 66.71;
H, 8.98; N, 15.68.
Typical experimental procedure for the synthesis of 4c
To
a
solution of 0.174
g
(1 mmol) 2-hydroxy-1,4-
naphthoquinone and 0.14 g (1 mmol) 4-chlorobenzaldehydes
in 1 ml water, 20 mol% thiourea-based organocatalyst I was
added and stirred under reux conditions for 15 minutes.
Aerwards, 0.155 g (1 mmol) 1,3-dimethyl-6-aminouracil was
introduced and stirring was continued until completion of the
reaction, as checked by TLC. The resulting mixture was cooled
at room temperature, and the solid was ltered off and washed
with water rst, then with 5 ml ethanol to afford the pure
product.
6-Amino-5-((1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-3-yl)-
(phenyl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 4a.
Yield 79%; red powdered solid; mp ¼ 250–251 ꢀC; IR (KBr): 3405,
3254, 2923, 1694, 1653, 1603, 1578, 1498, 1345, 967, 878, 755
cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d 13.20 (s, 1H), 8.03 (d, J ¼
8.0 Hz, 1H), 8.00 (d, J ¼ 8.0 Hz, 1H), 7.85 (t, J ¼ 8.0 Hz, 1H), 7.82
(t, J ¼ 8.0 Hz, 1H), 7.27–7.17 (m, 5H), 7.15 (s, 2H), 5.86 (s, 1H),
3.38 (s, 3H), 3.15 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6): d
185.9, 181.0, 163.6, 158.5, 154.4, 150.1, 138.3, 134.3, 133.4, 131.7,
130.5, 128.0, 126.6, 126.0, 125.6, 123.4, 100.4, 85.6, 34.7, 30.4,
Conclusions
We have synthesized a bifunctional thiourea-based organo-
catalyst and explored its application in the one-pot three
component reaction of aldehyde, 1,3-dimethyl-6-aminouracil
and 2-hydroxy-1,4-naphthoquinone/4-hydroxycoumarin in
aqueous medium, for the synthesis of diverse tri-substituted
methane derivatives with biologically active moieties such as
pyrimidine and naphthoquinone/coumarin as substituents. In
addition there are free –OH, –NH2 and CO groups in our
product molecules, which can be explored as ligands in coor-
dination chemistry as well as in heterocyclic chemistry for
further functionalization, or for the synthesis of fused hetero-
cycles. Studies towards the application of this methodology are
under way.
Experimental
Starting materials and solvents are commercially available and 28.1 ppm; anal. calcd for C23H19N3O5 (417.41): C, 66.18; H, 4.59;
were used without further purication. The purity of the N, 10.07; found: C, 66.26; H, 4.62; N, 10.20.
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Table 3 Synthesis of tri-substituted methane derivativesa containing
aminouracil and the hydroxynaphthoquinone moiety
154.4, 150.1, 134.9, 134.5, 134.1, 133.3, 131.7, 130.6, 128.6, 126.5,
126.0, 125.6, 123.5, 85.9, 34.3, 30.3, 28.0, 20.5 ppm; anal. calcd
for C24H21N3O5 (431.44): C, 66.81; H, 4.91; N, 9.74; found: C,
66.88; H, 4.94; N, 9.86.
6-Amino-5-((4-chlorophenyl)(1,4-dihydro-2-hydroxy-1,4-dioxo
naphthalen-3-yl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-
dione 4c. Yield 85%; red solid; mp ¼ 254–255 ꢀC; IR (KBr): 3385,
3261, 2987, 1702, 1663, 1605, 1580, 1489, 1342, 928, 836, 776
cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d 13.24 (s, 1H), 8.00 (d, J ¼
8.0 Hz, 1H), 7.97 (d, J ¼ 8.0 Hz, 1H), 7.81 (t, J ¼ 8.0 Hz, 1H), 7.78
(t, J ¼ 8.0 Hz, 1H), 7.29–7.27 (m, 4H), 7.23 (s, 2H), 5.84 (s, 1H),
3.38 (s, 3H), 3.15 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6): d
185.8, 180.9, 163.6, 158.5, 154.4, 150.1, 137.7, 134.2, 133.4,
131.7, 130.6, 130.2, 128.7, 127.8, 126.0, 125.6, 123.2, 85.4, 34.4,
30.4, 28.2 ppm; anal. calcd for C23H18ClN3O5 (451.86): C, 61.14;
H, 4.02; N, 9.30; found: C, 61.22; H, 4.05; N, 9.44.
6-Amino-5-((1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-3-yl)-
(4-nitrophenyl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione
4d. Yield 73%; yellow crystalline solid; mp ¼ 278–279 ꢀC; IR (KBr):
3397, 3241, 2929, 1697, 1665, 1603, 1556, 1473, 1351, 963, 810, 756
cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d 13.14 (s, 1H), 8.08 (d, J ¼
8.0 Hz, 2H), 8.00 (d, J ¼ 8.0 Hz, 1H), 7.97 (d, J ¼ 8.0 Hz, 1H), 7.85–
7.75 (m, 2H), 7.54 (d, J ¼ 8.0 Hz, 2H), 7.25 (s, 2H), 5.83 (s, 1H), 3.38
(s, 3H), 3.15 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6): d 185.8,
181.2, 163.6, 158.5, 154.4, 150.1, 147.7, 145.7, 134.4, 133.5, 131.7,
130.6, 128.2, 126.1, 125.7, 123.8, 110.9, 85.9, 35.3, 30.4, 28.2 ppm;
anal. calcd for C23H18N4O7 (462.41): C, 59.74; H, 3.92; N, 12.12;
found: C, 59.82; H, 3.88; N, 12.25.
6-Amino-5-((1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-3-yl)-
(4-methoxyphenyl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-
ꢀ
dione 4e. Yield 78%; orange solid; mp ¼ 247–248 C; IR (KBr):
3394, 3230, 2920, 1695, 1656, 1608, 1565, 1472, 1343, 965, 814,
773 cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d 13.18 (s, 1H), 8.02 (d,
J ¼ 8.0 Hz, 1H), 7.99 (d, J ¼ 8.0 Hz, 1H), 7.85 (t, J ¼ 8.0 Hz, 1H),
7.81 (t, J ¼ 8.0 Hz, 1H), 7.16 (s, 2H), 7.11 (d, J ¼ 8.0 Hz, 2H), 6.80
(d, J ¼ 8.0 Hz, 2H), 5.78 (s, 1H), 3.72 (s, 3H), 3.37 (s, 3H), 3.15 (s,
3H) ppm; 13C NMR (100 MHz, DMSO-d6): d 185.0, 181.2, 162.4,
158.0, 153.9, 150.4, 142.9, 134.4, 133.2, 131.8, 130.5, 129.7,
129.2, 127.9, 125.9, 125.4, 121.4, 86.5, 58.8, 35.1, 29.9, 27.9 ppm;
anal. calcd for C24H21N3O6 (447.44): C, 64.42; H, 4.73; N, 9.39;
found: C, 64.49; H, 4.77; N, 9.53.
a
Isolated yield.
6-Amino-5-(cyclohexyl(1,4-dihydro-2-hydroxy-1,4-dioxonaph-
thalen-3-yl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione
4f. Yield 67%; orange red solid; mp ¼ 201–202 ꢀC; IR (KBr):
3372, 3239, 2920, 1697, 1670, 1608, 1579, 1371, 975, 861, 752
cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d 14.08 (s, 1H), 7.97 (d, J ¼
8.0 Hz, 1H), 7.92 (d, J ¼ 8.0 Hz, 1H), 7.78 (t, J ¼ 8.0 Hz, 1H), 7.75
(t, J ¼ 8.0 Hz, 1H), 7.23 (s, 2H), 3.82 (d, J ¼ 8.0 Hz, 1H), 3.34 (s,
3H), 3.19 (s, 3H), 1.59–1.52 (m, 5H), 1.12–1.01 (m, 4H), 0.76–0.73
(m, 2H) ppm; 13C NMR (100 MHz, DMSO-d6): d 186.8, 180.9,
164.2, 158.2, 154.8, 152.7, 149.8, 134.1, 133.4, 131.2, 130.5,
125.9, 124.0, 85.2, 33.7, 31.5, 30.9, 29.9, 28.1, 27.6, 26.1 ppm;
anal. calcd for C23H25N3O5 (423.46): C, 65.24; H, 5.95; N, 9.92;
found: C, 65.32; H, 5.92; N, 10.04.
Scheme 3 The three component reaction of 4-hydroxycoumarin,
aldehyde and 1,3-dimethyl-6-aminouracil.
6-Amino-5-((1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-3-yl)-
(p-tolyl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione
4b.
Yield 81%; orange solid; mp ¼ 217–218 ꢀC; IR (KBr): 3421, 3247,
2921, 1698, 1661, 1607, 1567, 1475, 1356, 915, 878, 752 cmꢁ1; 1H
NMR (400 MHz, DMSO-d6): d 13.28 (s, 1H), 8.03 (d, J ¼ 8.0 Hz,
1H), 8.00 (d, J ¼ 8.0 Hz, 1H), 7.83 (t, J ¼ 8.0 Hz, 1H), 7.79 (t, J ¼
8.0 Hz, 1H), 7.19 (s, 2H), 7.09 (d, J ¼ 8.0 Hz, 2H), 7.04 (d, J ¼ 8.0
Hz, 2H), 5.79 (s, 1H), 3.40 (s, 3H), 3.17 (s, 3H), 2.27 (s, 3H) ppm;
13C NMR (100 MHz, DMSO-d6): d 186.0, 181.0, 163.7, 158.7,
6-Amino-5-((4-uorophenyl)(1,4-dihydro-2-hydroxy-1,4-diox-
onaphthalen-3-yl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-
dione 4g. Yield 80%; red crystalline solid; mp ¼ 241–242 ꢀC; IR
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Table 4 Synthesis of tri-substituted methane derivativesa containing
aminouracil and the hydroxycoumarin moiety
6-Amino-5-((4-bromophenyl)(1,4-dihydro-2-hydroxy-1,4-diox-
onaphthalen-3-yl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-
dione 4h. Yield 79%; orange solid; mp ¼ 251–252 ꢀC; IR (KBr):
3393, 3210, 2921, 1680, 1650, 1603, 1573, 1488, 1343, 905, 835,
756 cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d 13.15 (s, 1H), 8.02 (d,
J ¼ 8.0 Hz, 1H), 7.99 (d, J ¼ 8.0 Hz, 1H), 7.85 (t, J ¼ 8.0 Hz, 1H),
7.81 (t, J ¼ 8.0 Hz, 1H), 7.41 (d, J ¼ 8.0 Hz, 2H), 7.21–7.19 (m,
4H), 5.82 (s, 1H), 3.37 (s, 3H), 3.15 (s, 3H) ppm; 13C NMR (100
MHz, DMSO-d6): d 185.7, 180.9, 163.5, 158.5, 154.4, 150.1, 138.2,
134.3, 133.5, 131.7, 130.8, 130.6, 129.2, 126.0, 125.7, 123.2,
118.7, 85.3, 34.5, 30.4, 28.2 ppm; anal. calcd for C23H18BrN3O5
(496.31): C, 55.66; H, 3.66; N, 8.47; found: C, 55.75; H, 3.62; N,
8.60.
6-Amino-5-((1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-3-yl)-
(4-isopropylphenyl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-
dione 4i. Yield 81%; orange red crystalline solid; mp ¼ 259–260
ꢀC; IR (KBr): 3389, 3237, 2950, 1705, 1655, 1607, 1578, 1462,
1341, 951, 841, 761 cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d 13.27
(s, 1H), 8.02 (d, J ¼ 8.0 Hz, 1H), 7.99 (d, J ¼ 8.0 Hz, 1H), 7.83 (t,
J ¼ 8.0 Hz, 1H), 7.79 (t, J ¼ 8.0 Hz, 1H), 7.21 (s, 2H), 7.15–7.08
(m, 4H), 5.80 (s, 1H), 3.38 (s, 3H), 3.16 (s, 3H), 2.86–2.79 (m, 1H),
1.16 (d, J ¼ 8.0 Hz, 6H) ppm; 13C NMR (100 MHz, DMSO-d6): d
185.9, 181.1, 163.6, 158.6, 154.4, 150.1, 145.5, 135.5, 134.3,
133.4, 131.7, 130.5, 126.6, 126.0, 125.9, 125.7, 123.7, 85.6, 34.4,
32.8, 30.4, 28.2, 23.9 ppm; anal. calcd for C26H25N3O5 (459.49):
C, 67.96; H, 5.48; N, 9.14; found: C, 68.05; H, 5.44; N, 9.28.
6-Amino-5-((3-bromophenyl)(1,4-dihydro-2-hydroxy-1,4-diox-
onaphthalen-3-yl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-
a
Isolated yield.
ꢀ
dione 4j. Yield 81%; yellow solid; mp ¼ 234–235 C; IR (KBr):
3420, 3366, 2920, 1763, 1715, 1665, 1648, 1575, 1492, 1378, 968,
1
812, 754 cmꢁ1; H NMR (400 MHz, DMSO-d6): d 13.26 (s, 1H),
8.01 (d, J ¼ 8.0 Hz, 1H), 7.82 (d, J ¼ 8.0 Hz, 1H), 7.79 (d, J ¼ 8.0
Hz, 1H), 7.38 (s, 1H), 7.18 (s, 2H), 7.33 (d, J ¼ 8.0 Hz, 1H), 7.19–
7.17 (m, 4H), 5.87 (s, 1H), 3.40 (s, 3H), 3.18 (s, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6): d 185.7, 180.9, 163.6, 158.5, 154.4,
150.0, 141.3, 134.0, 133.2, 131.7, 130.6, 129.8, 129.2, 128.5,
126.0, 122.8, 121.7, 85.3, 34.5, 30.3, 28.0 ppm; anal. calcd for
C
23H18BrN3O5 (496.31): C, 55.66; H, 3.66; N, 8.47; found: C,
55.75; H, 3.70; N, 8.60.
6-Amino-5-((1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-3-yl)-
(3-nitrophenyl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-
dione 4k. Yield 78%; red crystalline solid; mp ¼ 224–225 ꢀC; IR
(KBr): 3371, 3230, 2941, 1685, 1670, 1605, 1552, 1465, 1350, 965,
Fig. 2 1H NMR and D2O exchanged 1H NMR spectra of 4c.
1
879, 765 cmꢁ1; H NMR (400 MHz, DMSO-d6): d 13.18 (s, 1H),
8.03 (t, J ¼ 8.0 Hz, 2H), 7.95 (d, J ¼ 8.0 Hz, 2H), 7.83–7.72 (m,
3H), 7.54 (t, J ¼ 8.0 Hz, 1H), 7.27 (s, 2H), 5.98 (s, 1H), 3.41 (s,
3H), 3.17 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6): d 185.6,
181.2, 163.5, 158.4, 154.5, 150.1, 148.0, 141.4, 134.2, 133.0,
131.7, 130.5, 129.2, 126.0, 125.3, 121.4, 110.9, 84.8, 34.8, 30.4,
28.1 ppm; anal. calcd for C23H18N4O7 (462.41): C, 59.74; H, 3.92;
N, 12.12; found: C, 59.82; H, 3.89; N, 12.26.
(KBr): 3396, 3246, 2922, 1738, 1687, 1665, 1659, 1608, 1578,
1371, 969, 893, 753 cmꢁ1 1H NMR (400 MHz, DMSO-d6): d
;
13.18 (s, 1H), 8.02 (d, J ¼ 8.0 Hz, 1H), 7.99 (d, J ¼ 8.0 Hz, 1H),
7.84 (t, J ¼ 8.0 Hz, 2H), 7.80 (t, J ¼ 8.0 Hz, 2H), 7.30–7.24 (m,
4H), 7.21 (s, 2H), 5.84 (s, 1H), 3.37 (s, 3H), 3.15 (s, 3H) ppm; 13
C
NMR (100 MHz, DMSO-d6): d 185.8, 181.0, 163.5, 158.5, 154.4,
150.1, 137.7, 134.3, 133.4, 131.7, 130.6, 130.2, 128.7, 127.9,
126.0, 125.7, 123.2, 85.4, 34.4, 30.4, 28.2 ppm; anal. calcd for
6-Amino-5-(1-(1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-3-
yl)butyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 4l. Yield
ꢀ
68%; red solid; mp ¼ 246–247 C; IR (KBr): 3375, 3215, 2958,
C
23H18FN3O5 (435.4): C, 63.45; H, 4.17; N, 9.65; found: C, 63.53;
1681, 1673, 1608, 1581, 1458, 1346, 968, 879, 794 cmꢁ1; 1H NMR
H, 4.20; N, 9.78.
(400 MHz, DMSO-d6): d 14.01 (s, 1H), 8.01 (d, J ¼ 8.0 Hz, 1H),
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131.9, 129.5, 127.1, 123.8, 123.6, 116.9, 115.8, 113.2, 104.4, 87.5,
54.7, 35.2, 30.2, 28.0 ppm. anal. calcd for C23H21N3O6 (435.43):
C, 63.44; H, 4.86; N, 9.65; found C, 63.51; H, 4.90; N, 9.76.
6-Amino-5-((2-chlorophenyl)(4-hydroxy-2-oxo-2H-chromen-3-
yl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 6c. Yield
ꢀ
83%; white crystalline solid; mp ¼ 227–228 C; IR (KBr): 3534,
3402, 3199, 2970, 1703, 1695, 1621, 1574, 1472, 1060, 1040, 862,
752 cmꢁ1; 1H NMR (400 MHz, CDCl3): d 13.68 (s, 1H), 8.03 (d, J ¼
8.0 Hz, 1H), 7.58 (t, J ¼ 8.0 Hz, 1H), 7.43 (d, J ¼ 8.0 Hz, 1H), 7.36–
7.31 (m, 3H), 7.26–7.16 (m, 2H), 6.48 (s, 2H), 5.75 (s, 1H), 3.57 (s,
3H), 3.30 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): d 167.4,
165.8, 164.7, 154.3, 152.3, 150.6, 135.9, 133.3, 132.5, 130.4,
129.2, 128.1, 126.5, 124.5, 124.4, 117.3, 116.2, 103.6, 89.4, 35.9,
30.1, 28.7 ppm; anal. calcd for C22H18N3O5 (439.85): C, 60.07; H,
4.12; N, 9.55; found C, 60.13; H, 4.15; N, 9.66.
Scheme 4 Proposed reaction mechanism.
6-Amino-5-((4-bromophenyl)(4-hydroxy-2-oxo-2H-chromen-
3-yl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 6d. Yield
86%; white crystalline solid; mp ¼ 237–238 C; IR (KBr): 3367,
7.96 (d, J ¼ 8.0 Hz, 1H), 7.78 (t, J ¼ 8.0 Hz, 1H), 7.74 (t, J ¼ 8.0 Hz,
1H), 7.27 (s, 2H), 4.22 (t, J ¼ 8.0 Hz, 1H), 3.37 (s, 3H), 3.12 (s,
3H), 2.19–2.07 (m, 2H), 1.26–1.21 (m, 2H), 0.88–0.85 (m, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6): d 185.6, 180.9, 164.3,
158.5, 154.2, 149.8, 133.8, 133.1, 131.4, 130.4, 125.8, 125.5,
124.8, 86.4, 30.7, 30.4, 30.2, 27.9, 21.1, 13.6 ppm; anal. calcd for
ꢀ
3196, 2979, 1734, 1704, 1660, 1573, 1487, 1444, 1065, 1045, 854,
758 cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d 13.95 (s, 1H), 7.87 (d,
J ¼ 8.0 Hz, 1H), 7.62 (t, J ¼ 8.0 Hz, 1H), 7.42–7.41 (m, 3H), 7.38
(s, 2H), 7.34 (t, J ¼ 8.0 Hz, 1H), 7.15 (d, J ¼ 8.0 Hz, 2H), 5.65 (s,
1H), 3.45 (s, 3H), 3.21 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-
d6): d 170.1, 165.9, 164.0, 155.1, 151.9, 149.9, 137.8, 132.2, 130.7,
128.6, 124.0, 123.7, 118.8, 116.9, 115.9, 104.1, 86.7, 35.7, 30.4,
28.1 ppm; anal. calcd for C22H18BrN3O5 (484.3): C, 54.56; H,
C
20H21N3O5 (383.4): C, 62.65; H, 5.52; N, 10.96; found: C, 62.73;
H, 5.55; N, 11.10.
Typical experimental procedure for the synthesis of 6b
To a solution of 0.162 g (1 mmol) 4-hydroxycoumarin and 0.136 3.75; N, 8.68; found C, 54.63; H, 3.78; N, 8.80.
g (1 mmol) 4-methoxybenzaldehydes in 1 ml water, 20 mol%
4-((6-Amino-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyr-
thiourea-based organocatalyst I was added and stirred under imidin-5-yl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)
reux conditions for 15 minutes. Aerwards, 0.155 g (1 mmol) benzonitrile 6e. Yield 82%; white crystalline solid; mp 221–223
1,3-dimethyl-6-aminouracil was introduced and stirring was ꢀC; IR (KBr): 3382, 3186, 2989, 1734, 1715, 1663, 1571, 1452,
continued until completion of the reaction, as checked by TLC. 1069, 1042, 860, 766 cmꢁ1 1H NMR (400 MHz, DMSO-d6): d
;
The resulting mixture was cooled at room temperature, and the 13.97 (s, 1H), 7.85 (d, J ¼ 8.0 Hz, 1H), 7.71 (d, J ¼ 8.0 Hz, 2H),
solid was ltered off and washed with water rst, then with 5 ml 7.66 (t, J ¼ 8.0 Hz, 1H), 7.46–7.35 (m, 6H), 5.72 (s, 1H), 3.39 (s,
ethanol to afford the pure product.
3H), 3.16 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6): d 165.6,
6-Amino-5-((1-4-hydroxy-2-oxo-2H-chromen-3-yl)(2-phenyl)
164.1, 163.8, 155.3, 151.9, 149.9, 144.9, 132.5, 131.9, 127.7,
ethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 6a. Yield, 76%; 124.3, 123.7, 118.9, 116.9, 116.1, 108.6, 104.2, 86.1, 36.5, 30.6,
ꢀ
white crystalline solid; mp ¼ 247–249 C; IR (KBr): 3529, 3428, 28.2 ppm; anal. calcd for C23H18N4O5 (430.41): C, 64.18; H, 4.22;
3155, 3017, 1708, 1671, 1623, 1490, 1378, 1049, 1013, 860, 765 N, 13.02; found C, 64.24; H, 4.26; N, 13.14.
cmꢁ1; 1H NMR (400 MHz, CDCl3): d 14.05 (s, 1H), 8.01 (d, J ¼ 8.0
6-Amino-5-((4-uorophenyl)(4-hydroxy-2-oxo-2H-chromen-3-
Hz, 1H), 7.51 (t, J ¼ 8.0 Hz, 1H), 7.30 (t, J ¼ 8.0 Hz, 1H), 7.26–7.22 yl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 6f. Yield
(m, 2H), 7.18 (d, J ¼ 8.0 Hz, 3H), 7.15–7.12 (m, 1H), 6.21 (s, 2H), 88%; white solid; mp ¼ 248–250 ꢀC; IR (KBr): 3389, 3194, 3077,
4.51 (t, J ¼ 8.0 Hz, 1H), 3.53–3.48 (m, 2H), 3.41 (s, 3H), 3.39 (s, 2952, 1735, 1705, 1675, 1565, 1493, 1060, 858, 755 cmꢁ1
;
1H
3H) ppm; 13C NMR (100 MHz, CDCl3): d 164.2, 163.5, 161.5, NMR (400 MHz, DMSO-d6): d 13.88 (s, 1H), 7.87 (d, J ¼ 8.0 Hz,
151.8, 151.6, 149.8, 140.1, 131.9, 128.2, 128.0, 126.1, 125.9, 1H), 7.61 (t, J ¼ 8.0 Hz, 1H), 7.38–7.32 (m, 4H), 7.20–7.17 (m,
124.1, 123.5, 115.9, 105.5, 88.5, 34.5, 30.3, 28.1, 26.9 ppm; anal. 2H), 6.99 (t, J ¼ 8.0 Hz, 2H), 5.65 (s, 1H), 3.47 (s, 3H), 3.21 (s, 3H)
calcd for C23H21N3O5 (419.43): C, 65.86; H, 5.05; N, 10.02; found ppm; 13C NMR (100 MHz, DMSO-d6): d 165.9, 164.0, 161.7,
C, 65.93; H, 5.09; N, 10.15.
159.3, 155.1, 151.9, 149.9, 133.9, 132.0, 128.0, 123.9, 123.7,
116.9, 115.8, 114.6, 104.3, 87.1, 35.4, 30.3, 28.1 ppm; anal. calcd
6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(4-methox-
yphenyl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 6b. for C22H18FN3O5 (423.39): C, 62.41; H, 4.29; N, 9.92; found C,
Yield 85%; white needle-like solid; mp ¼ 191–194 ꢀC; IR (KBr): 62.48; H, 4.32; N, 10.03.
3555, 3346, 3184, 2972, 1691, 1655, 1608, 1573, 1443, 1071,
1032, 859, 763 cmꢁ1; 1H NMR (400 MHz, DMSO-d6): d 13.88 (s,
Acknowledgements
1H), 7.88 (d, J ¼ 8.0 Hz, 1H), 7.59 (t, J ¼ 8.0 Hz, 1H), 7.36–7.30
(m, 4H), 7.06 (d, J ¼ 8.0 Hz, 2H), 6.77 (d, J ¼ 8.0 Hz, 2H), 5.63 (s, We are grateful to NIT Patna and the Department of Science and
1H), 3.74 (s, 3H), 3.46 (s, 3H), 3.23 (s, 3H) ppm. 13C NMR (100 Technology India for nancial support with Sanction No. SR/FT/
MHz, DMSO-d6): d 166.2, 164.0, 163.4, 157.2, 154.9, 151.9, 149.9, CS-008/2010. The authors are grateful to IIT Patna and the SAIF-
66838 | RSC Adv., 2015, 5, 66833–66839
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