First InCl3-catalyzed, three-component coupling of aldehydes, -naphthol, and 6-amino-1,3-dimethyluracil to functionalized naphthopyranopyrimidines

Article abstract of DOI:10.1055/s-0029-1219574

Indium(III) chloride was found to be a highly effective and efficient catalyst for the three-component, one-pot coupling of aldehydes, -naphthol, and 6-amino-1,3-dimethyluracil under solvent-free conditions to give 8,10-dimethyl-12-aryl-12H-naphtho[1,2:5,6]pyrano[2,3-d]pyrimidine-9,11-diones in high yields for the first time. No co-catalyst or activator is required. Water and ammonia are the only byproducts in the reactions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219574

LETTER
1133
First InCl3-Catalyzed, Three-Component Coupling of Aldehydes, b-Naphthol,
and 6-Amino-1,3-dimethyluracil to Functionalized
Naphthopyranopyrimidines
S
ynthesis of Funct
a
ionalized N
n
a
phthopyran
e
opyrimidin
s
es h Chandra Nandi, Subhasis Samai, M. S. Singh*
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
Fax +91(542)2368127; E-mail: mssinghbhu@yahoo.co.in
Received 24 December 2009
NPSR may represent a novel drug target for the treatment
Abstract: Indium(III) chloride was found to be a highly effective
and efficient catalyst for the three-component, one-pot coupling of
aldehydes, b-naphthol, and 6-amino-1,3-dimethyluracil under sol-
vent-free conditions to give 8,10-dimethyl-12-aryl-12H-naph-
tho[1¢,2¢:5,6]pyrano[2,3-d]pyrimidine-9,11-diones in high yields
for the first time. No co-catalyst or activator is required. Water and
ammonia are the only byproducts in the reactions.
of sleep and anxiety disorders.9
The utility of indium(III) salts as Lewis acids in organic
synthesis has received a great deal of interest due to their
relatively low toxicity, stability in air and water, opera-
tional simplicity, and strong tolerance to oxygen- and ni-
trogen-containing substrates and functional groups.10 It is
evident from the recent literature that indium trichloride11
has invoked enormous interest as a green and potential
Lewis acid catalyst to construct carbon–carbon and car-
bon–heteroatom bonds in various organic transformations
such as Mukaiyama aldol,12 Diels–Alder,13 aza-Michael,14
Friedel–Crafts,15 and ring-opening reactions of epoxides
with nucleophiles.16 It has received considerable attention
due to its cost effectiveness, ease of handling, good reac-
tivity, and remarkable ability to suppress side reactions in
acid-sensitive substrates.
Key words: multicomponent reaction, one-pot synthesis, InCl3,
naphthopyranopyrimidine
The continual upsurge in facile, convenient, and nonpol-
luting synthetic procedures urges chemists to increase
tools of their arsenal. One approach to address this chal-
lenge involves the development of environmentally be-
nign multicomponent procedures. In synthetic organic
chemistry, multicomponent reactions1 (MCR) have
gained considerable popularity in recent years due to its
flexible, convergent, and atom-efficient nature. They pro-
vide efficient access to complex molecules and an ideal
platform for rapid generation of both complexity and di-
versity in a collection of compounds with predefined
functionality. Moreover, MCR are an ideal synthetic tool
to generate multiple molecular scaffolds and to increase
structural and skeletal diversity.
OMe
MeO
NH
N
O
N
N
O
Among nitrogen-containing heterocycles, pyrimidines
represent one of the most prevalent heterocycles found in
natural products. The complementarity of convergent ap-
proaches and direct functionalization of the pyrimidines
scaffold facilitates the generation of a wide range of func-
tionalized pyrimidine derivatives.2 The pyranopyrimidines
have received special attention due to the wide range of
useful physiological3 and biological properties such as an-
timicrobial,4 analgesic, and anticonvulsant.5 Pyranopyri-
midines fused with coumarin ring are also used as
fungicides6 and herbicides.7 Naphthopyranopyrimidines
are biologically interesting compounds with antibacterial
Figure 1 Neuropeptide-S receptor
These findings have prompted us to develop a new and ef-
ficient one-pot multicomponent protocol to prepare a se-
ries of novel naphthopyranopyrimidines. We report herein
the first (to the best of our knowledge) three-component
coupling using aldehydes, 2-naphthol, and 6-amino-1,3-
dimethyluracil for the formation of 8,10-dimethyl-12-
aryl-12H-naphtho[1¢,2¢:5,6]pyrano[2,3-d]pyrimidine-
9,11-diones in the presence of InCl3 as effective and effi-
cient catalyst under solvent-free conditions.
and antifungal activities.8 Neuropeptide S receptor As part of an ongoing development of efficient protocols
(NPSR, Figure 1), previously known as GPR154, is high- for the preparation of substituted heterocycles and in con-
ly expressed in brain areas that have been implicated in tinuation of our recently reported work on MCR,17 we
modulation of arousal, stress, and anxiety. Therefore, have now discovered technically simple, high-yielding,
solvent-free conditions for the synthesis of novel 8,10-
dimethyl-12-aryl-12H-naphtho[1¢,2¢:5,6]pyrano[2,3-
d]pyrimidine-9,11-diones using InCl3 as catalyst
SYNLETT 2010, No. 7, pp 1133–1137
Advanced online publication: 05.03.2010
DOI: 10.1055/s-0029-1219574; Art ID: G37909ST
x
x.
x
x.
2
0
1
0
(Scheme 1). The reaction occurred via the in situ forma-
tion of ortho-quinone methide,18 a highly reactive and
© Georg Thieme Verlag Stuttgart · New York

1134
G. C. Nandi et al.
LETTER
R1
CHO
O
OH
+
Me
O
InCl3, 120 °C
solvent-free
O
N
+
Me
O
N
H2N
N
R1
Me
O
N
1
2
3
4
Me
Scheme 1 Synthesis of naphthopyranopyrimidines
ephemeral intermediate, which has been used in many tion by carrying out at different temperatures using 35
tandem processes19 and [4+2] cycloaddition with variety mol% of InCl3. It was found that at 100 °C the reaction
of dienophiles20 that have been extensively harnessed by proceeds slowly taking longer time for completion giving
nature.
lower yield and at 130 °C no significant improvement ei-
ther in time or yield was observed (Table 1).
In order to compare the efficiency and effectiveness of the
catalysts, the three-component condensations of 2-naph-
thol, aldehyde, and 6-amino-1,3-dimethyluracil were per-
formed in refluxing dichloromethane by using InCl3 and
P2O5 separately. InCl3 provides good yield after a long re-
action time (24 h). On the other hand, the byproduct aryl-
14H-dibenzo[a,j]xanthene 5 was obtained as major prod-
uct when P2O5 was used as catalyst (Scheme 2). Then it
was decided to carry out the reactions under solvent-free
conditions with above both catalysts. To our delight, with
InCl3 the reaction proceeded smoothly under solvent-free
conditions producing the desired product within 40 min-
utes. Whereas, with P2O5 the desired product 4 obtained
was in minor amount, and the undesired side product aryl-
14H-dibenzo[a,j]xanthene 5 was formed in major amount
(Scheme 2).
Table 1 Optimization of the Reaction Conditionsa
Entry
Catalyst (mol%) Temp (°C) Time (min) Yield (%)
1
2
3
4
5
6
7
no catalyst
InCl3 (20)
InCl3 (30)
InCl3 (35)
InCl3 (40)
InCl3 (35)
InCl3 (35)
120
120
120
120
120
100
130
240
60
40
25
25
65
25
0
45
61
78
72
56
74
a 4-Nitrobenzaldehyde (1.0 mmol), 2-naphthol (1.0 mmol), 6-amino-
1,3-dimethyluracil (1.2 mmol).
A test reaction using 2-naphthol, 4-nitrobenzaldehyde,
and 6-amino-1,3-dimethyluracil at 120 °C in the absence
of InCl3 was performed in order to establish the real effec-
tiveness of the catalyst. It was found that no conversion to
product was obtained even after 4 hours of heating. To op-
timize the catalyst loading, a model reaction using 2-
naphthol, 4-nitrobenzaldehyde, and 6-amino-1,3-dimeth-
yluracil at 120 °C was carried out under different catalyst
percentages (20 mol%, 30 mol%, 35 mol%, and 40 mol%
of InCl3; Table 1). It was observed that 35 mol% loading
of the catalyst provides the maximum yield in minimum
time (Table 1, entry 4). Higher percentage loading of the
catalyst neither increased the yield nor lowered the reac-
tion time. We next optimized the temperature of the reac-
Using the optimized reaction conditions, the efficiency of
this protocol was studied for the synthesis of various 8,10-
dimethyl-12-aryl-12H-naphtho[1¢,2¢:5,6]pyrano[2,3-
d]pyrimidine-9,11-diones, and the results are summarized
in Table 2. In most cases, the reaction proceeded with
high efficiency and broad functional-group tolerance. To
expand the scope of aldehyde substrates, various mono-
and disubstituted aromatic aldehydes containing both
electron-withdrawing and electron-donating substituents
were used, which displayed high reactivity under the op-
timized reaction conditions and generated the desired
products in high yields. However, unfortunately, when
R1
R1
CHO
O
O
OH
+
Me
O
Me
O
N
N
+
+
H2N
N
O
N
O
R1
Me
Me
1
2
3
4
5
catalyst InCl3
catalyst P2O5
exclusive
minor
not formed
major
Scheme 2 Coupling of aldehydes, b-naphthol, and 6-amino-1,3-dimethyluracil using InCl3 and P2O5
Synlett 2010, No. 7, 1133–1137 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized Naphthopyranopyrimidines
1135
some aliphatic aldehydes such as cinnamaldehyde, isobu- methide intermediate (o-QM) A, which was formed by the
tyraldehyde, and cyclohexanaldehyde were used in this nucleophilic addition of 2-naphthol to aldehyde. InCl3 as
protocol under the above optimized conditions, the de- Lewis acid plays a role in increasing the electrophilic
sired products could not be obtained.
character of the starting aldehyde and stabilizing the o-
QM intermediate by the coordination of oxygen lone elec-
tron pair with In(III).21 Subsequent Michael addition of
the o-QM A with 6-amino-1,3-dimethyluracil provides
the intermediate B that on subsequent intramolecular cy-
clization followed by deamination afforded the naphtho-
pyranopyrimidines 4. To the best of our knowledge, this
type of ring-closing deamination mediated by InCl3 in
one-pot leading to novel naphthopyranopyrimidines has
not been previously reported.
Table 2 Synthesis of Naphthopyranopyrimidines 4
Entry
1
Aldehyde
Product
4a
4b
4c
Time (min) Yield (%)
Ph
25
25
25
25
25
25
25
25
30
25
20
45
45
40
35
35
40
40
80
78
81
76
79
77
83
72
78
81
83
69
67
68
67
69
72
70
2
4-O2NC6H4
2-O2NC6H4
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
3
4
4d
4e
In conclusion, we have developed a highly efficient InCl3-
catalyzed, three-component, one-pot protocol22 for the
synthesis of 8,12-dihydro-8,10-dimethyl-12-aryl-9H-
naphtho[1¢,2¢:5,6]pyrano[2,3-d]pyrimidine-9,11-(10H)-
dione via condensation of aldehydes, 2-naphthol, and 6-
amino-1,3-dimethyluracil. The advantages of this method
are short reaction times, high yields, mild reaction condi-
tions, easy purification, and economic availability of the
catalyst. Water and ammonia are the only byproducts in
this three-component reaction. Further studies to extend
such easy-to-handle protocols are still in progress in our
laboratory.
5
6
4f
7
2-ClC6H4
4g
4h
4i
8
2,4-Cl2C6H4
4-MeC6H4
9
10
11
12
13
14
15
16
17
18
4-BrC6H4
4j
4-FC6H4
4k
4l
4-HOC6H4
3-HOC6H4
2-HOC6H4
5-Br-2-HOC6H3
5-O2N-2-HOC6H3
2-HO-3-MeOC6H3
2-HO-3-EtOC6H3
4m
4n
4o
4p
4q
4r
Acknowledgment
We gratefully acknowledge the financial support in the form of se-
nior research fellowships to G.C.N. and S.S. from Council of Scien-
tific and Industrial Research (CSIR), New Delhi, India.
References and Notes
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A plausible mechanism for the synthesis of naphthopyra-
nopyrimidines catalyzed by InCl3 has been proposed
(Scheme 3). The reaction proceeds via the ortho-quinone
O
Me
O
Me
InCl3
N
R
N
InCl3
OH
O
NH2
O
R
R
H
1
H
••
OH
O
InCl3
– H2O
A
2
O
Me
N
Me
O
H
O
N
Me
N
R
O
O
R
R
N
Me
Me
HN
N
NH2
H
InCl3
– NH3
O
OH
O
N
O
Me
4
B
Scheme 3 Tentative mechanism for the formation of naphthopyranopyrimidines
Synlett 2010, No. 7, 1133–1137 © Thieme Stuttgart · New York

1136
G. C. Nandi et al.
LETTER
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dimethyl-12-aryl-9H-naphtho[1¢,2¢:5,6]pyrano[2,3-
d]pyrimidine-9,11-(10H)-dione (4)
The aldehyde (1.0 mmol), 6-amino-1,3-dimethyluracil (1.2
mmol), and 2-naphthol (1.0 mmol) were ground in a mortar.
The catalyst InCl3 (35 mol%) was added to the reaction
mixture and further ground nicely for additional 15 min. The
whole reaction mixture was heated in an oil bath at 120 °C
for the stipulated period of time (Table 1) till the completion
of the reaction (monitored by TLC). Water (50 mL) was
added to the reaction mixture to remove unreacted reactants,
and the product was extracted with EtOAc (3 × 20 mL). The
organic layer was dried over anhyd MgSO4, and the solvent
was evaporated under vacuum. The residue obtained was
purified by column chromatography on silica gel using
EtOAc–n-hexane (1:4) to afford the pure desired product.
Finally the products were recrystallized from MeOH.
Spectral and Analytical Data of Some Newly Synthesized
Compounds
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12-(4-Methoxyphenyl)-8,12-dihydro-8,10-dimethyl-9H-
naphtho[1¢,2¢:5,6]pyrano[2,3-d]pyrimidine-9,11-(10H)-
dione (4d)
White solid; Rf = 0.40 (EtOAc–hexane, 1:4); mp 257–
258 °C. IR (KBr): 3057, 2948, 1708, 1650, 1587, 1481
cm–1. 1H NMR (300 MHz, DMSO-d6): d = 8.03–7.93 (m, 3
H), 7.61–7.43 (m, 3 H), 7.24 (d, J = 7.8 Hz, 2 H), 6.74 (d,
J = 7.8 Hz, 2 H), 5.61 (s, 1 H), 3.62 (s, 3 H), 3.50 (s, 3 H),
3.16 (s, 3 H). 13C NMR (75 MHz, DMSO-d6): d = 161.4,
157.7, 151.8, 150.1, 146.6, 135.9, 131.3, 130.3, 129.1,
128.9, 128.2, 127.0, 125.1, 123.4, 117.0, 116.3, 113.3, 90.9,
54.7, 34.7, 28.7, 27.7. MS–FAB: m/z = 401 [M + H]+. Anal.
Calcd for C24H20N2O4: C, 71.99; H, 5.03; N, 7.00. Found: C,
71.78; H, 4.91; N, 6.88.
12-(3-Hydroxyphenyl)-8,12-dihydro-8,10-dimethyl-9H-
naphtho[1¢,2¢:5,6]pyrano[2,3-d]pyrimidine-9,11-(10H)-
dione (4m)
White solid; Rf = 0.40 (EtOAc–hexane, 2:5); mp 293–
294 °C. IR (KBr): 3409, 3054, 2951, 1708, 1642, 1590, 1478
cm–1. 1H NMR (300 MHz, CDCl3): d = 7.95–7.82 (m, 3 H),
7.43–7.37 (m, 3 H), 7.09 (t, J = 8.1 Hz, 1 H), 6.90–6.88 (m,
2 H), 6.60 (d, J = 7.2 Hz, 1 H), 5.77 (s, 1 H), 5.23 (s, 1 H),
3.60 (s, 3 H), 3.33 (s, 3 H). 13C NMR (75 MHz, CDCl3):
d = 161.9, 155.6, 152.4, 150.6, 147.2, 145.5, 131.7, 130.9,
129.6, 129.5, 128.4, 127.5, 125.5, 123.9, 120.5, 116.2,
115.3, 113.9, 106.8, 91.3, 35.7, 29.0, 28.2. MS–FAB:
m/z = 387 [M + H]+. Anal. Calcd for C23H18N2O4: C, 71.49;
H, 4.70; N, 7.25. Found: C, 71.41; H, 4.67; N, 7.12.
12-(5-Bromo-2-hydroxyphenyl)-8,12-dihydro-8,10-
dimethyl-9H-naphtho[1¢,2¢:5,6]pyrano[2,3-
(14) Loh, T.-P.; Wei, L.-L. Synlett 1998, 975.
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(17) (a) Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S.
Tetrahedron 2009, 65, 7129. (b) Nandi, G. C.; Samai, S.;
Kumar, R.; Singh, M. S. Tetrahedron Lett. 2009, 50, 7220.
(c) Samai, S.; Nandi, G. C.; Kumar, R.; Singh, M. S.
Tetrahedron Lett. 2009, 50, 7096. (d) Samai, S.; Nandi, G.
d]pyrimidine-9,11-(10H)-dione (4o)
White solid; Rf = 0.40 (EtOAc–hexane, 2:3); mp 291–
Synlett 2010, No. 7, 1133–1137 © Thieme Stuttgart · New York

LETTER
292 °C. IR (KBr): 3112, 2951, 2930, 1703, 1643, 1591, 1476
Synthesis of Functionalized Naphthopyranopyrimidines
1137
131.4, 129.8, 129.2, 128.4, 127.6, 125.9, 125.5, 123.4,
cm–1. 1H NMR (300 MHz, DMSO-d6): d = 9.18 (s, 1 H),
8.25–8.03 (m, 4 H), 7.83–7.77 (m, 2 H), 7.65–7.45 (m, 3 H)
6.55 (s, 1 H), 3.68 (s, 3 H), 3.35 (s, 3 H). 13C NMR (75 MHz,
DMSO-d6): d = 161.1, 153.8, 152.7, 150.0, 146.8, 132.9,
132.6, 131.1, 130.5, 130.3, 129.3, 128.5, 127.2, 125.2,
123.5, 118.1, 116.8, 116.3, 110.1, 88.6, 30.7, 28.9, 27.7.
MS–FAB: m/z = 465 [M + H]+. Anal. Calcd for
C23H17BrN2O4: C, 59.37; H, 3.68; N, 6.02. Found: C, 59.19;
H, 3.58; N, 5.91.
12-(2-Hydroxy-5-nitrophenyl)-8,12-dihydro-8,10-
dimethyl-9H-naphtho[1¢,2¢:5,6]pyrano[2,3-
d]pyrimidine-9,11-(10H)-dione (4p)
Yellow solid; Rf = 0.40 (EtOAc–hexane, 2:3); mp 215–
217 °C. IR (KBr): 3320, 2951, 2930, 1709, 1646, 1586, 1470
cm–1. 1H NMR (300 MHz, DMSO-d6): d = 9.66 (s, 1 H),
8.16–8.09 (m, 2 H), 7.97–7.31 (m, 5 H), 6.91–6.88 (m, 2 H),
6.10 (s, 1 H), 3.50 (s, 3 H), 3.02 (s, 3 H). 13C NMR (75 MHz,
DMSO-d6): d = 161.2, 153.9, 152.7, 150.2, 147.3, 133.1,
122.8, 122.3, 118.9, 117.3, 116.4, 87.6, 29.6, 29.2, 27.7.
MS–FAB: m/z = 432 [M + H]+. Anal. Calcd for C23H17N3O6:
C, 64.04; H, 3.97; N, 9.74. Found: C, 63.91; H, 3.85; N, 9.72.
12-(3-Ethoxy-2-hydroxyphenyl)-8,12-dihydro-8,10-
dimethyl-9H-naphtho[1¢,2¢:5,6]pyrano[2,3-
d]pyrimidine-9,11-(10H)-dione (4r)
White solid; Rf = 0.40 (EtOAc–hexane, 3:7); mp 208–
209 °C. IR (KBr): 3225, 3061, 2963, 2928, 1702, 1671,
1590, 1482 cm–1. 1H NMR (300 MHz, CDCl3): d = 9.41 (s,
1 H), 7.69–7.67 (m, 2 H), 7.46–7.15 (m, 4 H), 6.87 (t, J = 7.8
Hz, 1 H), 6.77 (d, J = 8.1 Hz, 1 H), 6.42 (d, J = 7.5 Hz, 1 H),
6.03 (s, 1 H), 4.21–4.10 (m, 2 H), 3.68 (s, 3 H), 3.30 (s, 3 H),
1.56 (t, J = 6.9 Hz, 3 H). 13C NMR (75 MHz, CDCl3):
d = 162.1, 153.4, 153.1, 150.1, 147.4, 139.1, 132.0, 130.1,
129.6, 129.0, 126.1, 125.9, 125.4, 123.2, 123.0, 122.4,
122.1, 111.2, 90.2, 52.1, 31.0, 28.9, 27.7, 14.8. MS–FAB:
m/z = 431 [M + H]+. Anal. Calcd for C25H22N2O5: C, 69.76;
H, 5.15; N, 6.51. Found: C, 69.69; H, 4.92; N, 6.32.
Synlett 2010, No. 7, 1133–1137 © Thieme Stuttgart · New York

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