Iodine-catalyzed three-component one-pot synthesis of naphthopyranopyrimidines under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2012.01.096

Iodine is found to be a highly efficient catalyst for the three-component coupling (3CC) of aldehydes, β-naphthol, and 1,3-dimethylbarbituric acid under solvent-free conditions to afford the corresponding 8,10-dimethyl-12-aryl- 12H-naphtho[1′,2′5,6]pyrano

Full text of DOI:10.1016/j.tetlet.2012.01.096

Tetrahedron Letters 53 (2012) 1738–1741
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iodine-catalyzed three-component one-pot synthesis
of naphthopyranopyrimidines under solvent-free conditions
K. Praveen Kumar a, S. Satyanarayana a, P. Lakshmi Reddy a, G. Narasimhulu b, Narender Ravirala a,
,
⇑
B.V. Subba Reddy b,
⇑
a Crop Protection Chemicals, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Iodine is found to be a highly efficient catalyst for the three-component coupling (3CC) of aldehydes,
b-naphthol, and 1,3-dimethylbarbituric acid under solvent-free conditions to afford the corresponding
8,10-dimethyl-12-aryl-12H-naphtho[10,205,6]pyrano[2,3-d]pyrimidine-9,11-diones in good yields with
high selectivity. The use of readily available iodine makes this method very simple, convenient, and
cost-effective.
Received 31 December 2011
Revised 20 January 2012
Accepted 22 January 2012
Available online 28 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
3CC Reaction
Molecular iodine
Naphthopyranopyrimidine
NPSR antagonists
The multi-component reactions are highly important because of
their wide range of applications in pharmaceutical chemistry for the
rapid generation of structural diversity in combinatorial libraries
for drug discovery.1 MCRs are extremely convergent, producing a
remarkably high increase of molecular complexity in just one
step.2,3 Naphthopyranopyrimidine and its derivatives are important
structural motifs in medicinal and pharmaceutical chemistry. They
are known to exhibit promising physiological4 and biological prop-
erties such as antimicrobial5 and anticonvulsant behavior.6 They are
also known to possess antibacterial and antifungal activities.7,8
Recently, Marugan et al. have reported the biological activity of
these molecules (Fig. 1) as antagonists for neuropeptide S receptor
(NPSR).9 The NPSR represents a novel drug targets for the treatment
of sleep, anxiety, and addiction disorders.10
Consequently, there have been some reports on the synthesis of
dibenzoxanthene derivatives using acid catalysts such as BF3ꢀOEt2,
Sr(OTf)2, and TBAF, more recently with InCl3.11 However, some of
these methods often involve long reaction times, harsh reaction
conditions and expensive catalysts. Thus, there is a need to develop
a simple and cost-effective protocol for the synthesis of naphtho-
pyranopyrimidines of biological importance.
O
O
O
NH
O
NH
N
N
N
N
O
N
II
I
Figure 1. Representative examples of biologically interesting naphthopyrano-
pyrimidines.
Recently, molecular iodine has received considerable attention
as inexpensive, non-toxic, and readily available catalyst for various
organic transformations affording the corresponding products with
high selectivity and in excellent yields. The mild Lewis acidity
associated with iodine has enhanced its use in organic synthesis
to perform several organic transformations using stoichiometric
levels to catalytic amounts.12
In continuation of our interest on catalytic application of
molecular iodine,13 and multi-component reactions (MCRs),14 we
herein report a simple and metal-free synthesis of naphthopyrano-
pyrimidines via a three-component reaction under solvent-free
conditions. Initially, we attempted the 3CC reaction between
2-naphthol, benzaldehyde, and 1,3-dimethylbarbutyric acid in the
presence of 10 mol % molecular iodine in acetonitrile at room tem-
perature (Scheme 1). However, no reaction was observed at room
temperature either in acetonitrile or ethanol. Then the reaction
To the best of our knowledge, this is the first report on the syn-
thesis of naphthopyranopyrimidines using molecular iodine under
solvent-free conditions via a three-component reaction.
⇑
Corresponding authors. Fax: +91 40 27160512.
E-mail addresses: raviralanarender@gmail.com (N. Ravirala), basireddy@iict.
res.in (B.V. Subba Reddy).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.096

K. Praveen Kumar et al. / Tetrahedron Letters 53 (2012) 1738–1741
1739
was performed at 80 °C in both solvents, however the desired naph-
thopyranopyrimidine 4a was obtained in very low yields along with
phenyl-14H-dibenzo[a,j]xanthene after a long reaction time (8 h). It
was found that keeping the reaction at lower temperature, that is,
less than 100 °C, aryl-14H-dibenzo[a,j]xanthene was predominant
even under solvent-free conditions using 10 mol % iodine. By
increasing the temperature to 120 °C, the reaction went to comple-
tion within 60 min and the desired naphthopyranopyrimidine 4a
was obtained in 82% yield (Scheme 1).
HO
O
O
N
I
2 (10 mol%)
+
O
O
O
º
120 C, neat
N
N
1
3
O
4a
O
N
2
Scheme 1. 3CC Reaction of 2-naphthol, benzaldehyde and 1,3-dimethylbarbutyric
acid.
Table 1
I2-catalyzed synthesis of naphthopyranopyrimidines via three-component reaction
Entry
Aldehyde
2-Naphthol
Producta
Time (min)
Yieldb (%)
CHO
OH
OH
a
60
82
O
N
N
N
N
N
O
O
O
O
O
CHO
Cl
b
60
60
80
60
75
72
84
73
Cl
O
N
O
CHO
OH
OH
OH
Br
c
Br
Cl
F
O
N
O
CHO
Cl
Cl
d
Cl
O
O
F
N
O
CHO
e
N
O
N
O
O
O
CHO
OH
OH
f
70
45
45
68
75
O
N
N
O
O
CHO
g
h
O
N
O
O
N
O
CHO
OH
Cl
Cl
67
O
N
N
O
(continued on next page)

1740
K. Praveen Kumar et al. / Tetrahedron Letters 53 (2012) 1738–1741
Table 1 (continued)
Entry
Aldehyde
2-Naphthol
Producta
Time (min)
Yieldb (%)
CHO
Br
OH
OH
Br
i
j
70
65
O
N
N
O
O
CHO
55
59
O
N
O
N
O
CHO
OH
NO2
k
55
86
O2N
O
N
N
O
O
CHO
OH
CN
NC
l
60
72
O
N
N
O
O
a
The products were characterized by NMR, IR and mass spectroscopy.
Yield refers to pure products after column chromatography.
b
The 3CC reaction was also performed using various amounts of
iodine. Initially, 5 mol % iodine was used to perform the reaction.
But it requires slightly long reaction time. Therefore, the loading
of the catalyst was gradually increased from 5 mol % to 50 mol %.
It was found that 10 mol % of I2 is optimal to carry out the
reactions in a short duration (45–80 min). The use of excess of
catalyst did not alter either reaction time or yield of the product.
Thus, the use of 10 mol % iodine at 120 °C is ideal to achieve
the desired product in good yields. However, in the absence of
1,3-dimethylbarbutyric acid, aryl-14H-dibenzo[a,j]xanthene was
formed exclusively in good yields. Next, we examined the reactiv-
ity of various catalysts such as FeCl3, Mn(OAc)3ꢀ2H2O and ceric
ammonium nitrate. Of these, molecular iodine was found to be
superior in terms of conversion. For example, 2-naphthol under-
went smooth electrophilic nitration along with the formation of
desired naphthopyranopyrimidine when CAN was used. Similarly,
a mixture of naphthopyranopyrimidine and aryl-14H-dibenzo[a,j]
xanthene was obtained with Mn(OAc)3ꢀ2H2O. However, in the
presence of FeCl3, the dimerization of 2-naphthol was prominent
than the expected product. Next, we decided to study the scope
of the reaction with respect to various aldehydes under optimized
conditions. Interestingly, a variety of aromatic aldehydes bearing
substitutions at ortho-, meta-, and para-positions participated well
Ph
O
O
N
OH
I2
O
H
+
H.O.
N
O
O
O
N
N
N
-H2O
O
N
O
O
OH
OH
Scheme 2. A plausible reaction pathway.
followed by cyclodehydration would give the desired naphthopyr-
anopyrimidine (Scheme 2).
In summary, we have demonstrated a metal-free approach for
the Biginelli-type three-component reaction for the synthesis of a
variety of pharmacologically potent naphthopyranopyrimidines
using a catalytic amount of molecular iodine. The advantages of
this method are short reaction times, good conversions, high selec-
tivity, and easy availability of the catalyst at low costs. Further
studies to extend such easy-to-handle protocols are still in pro-
gress in our laboratory.
15
in this 3CC reaction (Table 1). This method was successful with
pharmacologically most prevalent substrates such as halogenated
aldehydes. Notably, sterically hindered ortho substituted alde-
hydes also participated effectively in this reaction. Both electron
rich as well as electron deficient substrates are found to be equally
effective for this conversion.
Acknowledgements
Mechanistically, we assume that the reaction proceeds via the
formation of ortho-quinonemethide from b-naphthol and alde-
hyde. Subsequent Michael addition of 1,3-dimethylbarbutyric acid
K.P., S.S. and G.N. are thankful to the Council of Scientific and
Industrial Research, New Delhi, India, for the award of fellowships.
P.L.R. is thankful to UGC, for the award of a fellowship.

K. Praveen Kumar et al. / Tetrahedron Letters 53 (2012) 1738–1741
ESI: m/z: 371 (M+H); HRMS calcd for
1741
C
23H18N2O3Na: 393.1215, found:
References and notes
393.1230. 4b: White solid; mp 274–276 °C; IR (KBr):
m 2923, 2852, 1704,
1675, 1591, 1226, 1174, 1087, 750 cmꢂ1 1H NMR (300 MHz, CDCl3): d 8.04 (d,
;
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J = 8.5 Hz, 1H), 7.87–7.78 (m, 2H), 7.48–7.40 (m, 2H), 7.35 (d, J = 9.1 Hz, 1H),
7.26 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 5.75 (s, 1H), 3.60 (s, 3H), 3.32 (s,
3H); 13C NMR (75 MHz, CDCl3): d 161.9, 152.2, 150.5, 147.1, 142.3, 132.5,
131.7, 130.7, 129.7, 129.6, 128.5, 127.5, 125.6, 123.7, 116.7, 116.3, 90.9, 35.4,
29.0, 28.2; MS-ESI: m/z: 405 (M+H); HRMS calcd for C23H18N2O3Cl: 405.1005,
found: 405.1001. 4c: White solid; mp 243–245 °C; IR (KBr):
m 2923, 2853,
1707, 1669, 1644, 1593, 1483, 1226, 506 cmꢂ1 1H NMR (500 MHz, CDCl3): d
;
7.85–7.77 (m, 3H), 7.43 (m, 2H), 7.34 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H),
7.19 (d, J = 8.8 Hz, 2H), 5.71 (s, 1H), 3.58 (s, 3H), 3.31 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 161.9, 152.2, 150.5, 147.1, 142.8, 131.7, 131.5, 130.7, 130.0, 129.7,
128.5, 127.5, 125.6, 123.7, 120.6, 116.6, 116.2, 90.8, 35.5, 29.0, 28.2; MS-ESI: m/
z: 471 (M+Na); HRMS calcd for C23H17N2O3NaBr: 471.0320, found: 471.0323.
4d: White solid; mp 219–221 °C; IR (KBr):
m
3057, 2925, 1710, 1647, 1594,
8.05 (d,
1482, 1228, 1178, 749, 722 cmꢂ1 1H NMR (300 MHz, CDCl3):
;
d
J = 8.3 Hz, 1H), 7.82–7.76 (m, 2H), 7.53–7.39 (m, 2H), 7.32–7.29 (m, 2H), 7.22
(s, 1H), 7.08 (dd, J = 8.3, 2.3 Hz, 1H), 6.01 (s, 1H), 3.63 (s, 3H), 3.30 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 161.6, 152.4, 150.4, 146.8, 139.7, 133.7, 133.0, 132.3,
131.5, 130.9, 129.9, 129.6, 128.6, 127.6, 127.4, 125.5, 123.7, 116.2, 89.9, 33.7,
29.0, 28.1; MS-ESI: m/z: 439 (M+H); HRMS calcd for C23H17N2O3Cl: 439.0616,
found: 439.0615. 4e: White solid; mp 305–307 °C; IR (KBr):
m 3064, 2922,
1707, 1672, 1645, 1596, 1484, 1450, 1228, 1164 cmꢂ1 1H NMR (300 MHz,
;
7. Joshi, K. C.; Jain, R.; Sharma, K. J. Indian Chem. Soc. 1988, 45, 202.
8. Bedair, A. H.; Emam, H. A.; El-Hady, N. A.; Ahmed, K. A. R.; El-Agrody, A. M.
Farmaco 2001, 56, 965.
9. McCoy, J. G.; Marugan, J. J.; Liu, K.; Zheng, W.; Southall, N.; Huang, W.; Heilig,
M.; Austin, C. P. ACS Chem. Neurosci. 2010, 1, 559.
CDCl3): d 7.88–7.78 (m, 3H), 7.48–7.39 (m, 2H), 7.37–7.24 (m, 3H), 6.86 (t,
J = 8.7 Hz, 2H), 5.75 (s, 1H), 3.60 (s, 3H), 3.32 (s, 3H); 13C NMR (75 MHz,
CDCl3+DMSO-d6): d 161.9, 152.2, 150.6, 147.1, 139.6, 131.8, 130.7, 129.8, 129.7,
128.6, 127.5, 125.6, 123.8, 117.0, 116.3, 115.4, 115.1, 91.2, 35.3, 29.1, 28.2; MS-
ESI: m/z: 389 (M+H); HRMS calcd for C23H18N2O3F: 389.1301, found: 389.1313.
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4f: White solid; mp 177–179 °C; IR (KBr):
m 2923, 2854, 1703, 1652, 1450,
1229, 1170, 1044 cmꢂ1 1H NMR (300 MHz, CDCl3): d 7.92 (d, J = 8.1 Hz, 1H),
;
11. (a) Laitinen, T.; Polvi, A.; Rydman, P.; Vendelin, J.; Pulkkinen, V.; Salmikangas,
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7.8 (d, J = 8.7 Hz, 2H), 7.5–7.39 (m, 2H), 7.33 (d, J = 8.9 Hz, 1H), 7.25–7.18 (m,
2H), 7.16–7.08 (m, 2H), 7.04–6.97 (m, 1H), 5.74 (s, 1H), 3.59 (s, 3H), 3.34 (s,
3H); 13C NMR (75 MHz, CDCl3): d 161.8, 157.0, 156.8, 152.2, 150.6, 147.0, 145.8,
131.7, 130.8, 139.8, 129.5, 129.4, 128.5, 127.4, 125.4, 123.8, 123.2, 123.1, 119.0,
118.6, 117.0, 116.6, 116.3, 91.1, 35.8, 29.0, 28.2; MS-ESI: m/z: 463 (M+H);
HRMS calcd for C29H23N2O4: 463.1657, found: 463.1650. 4g: White solid; mp
200–202 °C; IR (KBr):
m ;
2922, 2854, 1700, 1639, 1487, 1230, 1175 cmꢂ1 1H
NMR (300 MHz, CDCl3): d 7.92 (d, J = 8.3 Hz, 1H), 7.81–7.75 (m, 2H), 7.47–7.32
(m,3H), 7.21–7.16 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 8.3 Hz, 2H), 5.71 (s, 1H), 3.58 (s,
3H), 3.31 (s, 3H), 2.22 (s, 3H); 13C NMR (75 MHz, CDCl3): d 161.5, 151.8, 150.3,
147.1, 140.9, 136.0, 131.7, 130.1, 129.3, 129.2, 128.4, 128.1, 127.4, 125.4, 124.2,
117.7, 116.1, 91.5, 35.5, 28.9, 28.1, 21.1; MS-ESI: m/z: 407 (M+Na); HRMS calcd
for C24H20N2O3Na: 407.1371, found: 407.1388. 4h: White solid; mp 222–
224 °C; IR (KBr):
m ;
2923, 1707, 1641, 1594, 1482, 1430, 1230, 1177, 741 cmꢂ1
1H NMR (300 MHz, CDCl3): d 7.89–7.79 (m, 3H), 7.51–7.39 (m, 4H), 7.18–7.05
(m, 3H), 5.75 (s,1H), 3.61 (s, 3H), 3.33 (s, 3H);13C NMR (75 MHz, CDCl3): d
161.8, 152.3, 150.5, 147.1, 145.7, 134.3, 131.8, 130.7, 129.8, 129.5, 128.6, 128.2,
127.6, 127.0, 126.7, 125.6, 123.7, 116.5, 116.3, 90.8, 35.8, 29.1, 28.2; MS-ESI: m/
z: 405 (M+H); HRMS Calcd for C23H18N2O3Cl: 405.1005, found: 405.0997. 4i:
White solid; mp 217–219 °C; IR (KBr):
m 2923, 1708, 1652, 1595, 1456, 1235,
1180 cmꢂ1 1H NMR (300 MHz, CDCl3): d 8.22 (d, J = 8.3 Hz, 1H), 7.77 (m, 2H),
;
7.53–7.46 (m, 2H), 7.43–7.17 (m, 3H), 7.11 (t, J = 7.2 Hz, 1H), 6.98–6.91 (m, 1H),
6.03 (s, 1H), 3.63 (s, 3H), 3.30 (s, 3H); 13C NMR (75 MHz, CDCl3): d 161.4, 157.2,
150.4, 146.8, 142.9, 133.5, 132.4, 132.0, 131.7, 131.3, 129.8, 128.5, 128.2, 127.7,
127.6, 125.6, 124.6, 123.7, 117.4, 90.7, 36.6, 29.1, 28.2; MS-ESI: m/z: 449
(M+H); HRMS calcd for C23H18N2O3Br: 449.0500, found: 449.0504. 4j: White
solid; mp 193–195 °C; IR (KBr):
m
3066, 2924, 1704, 1644, 1587, 1486, 1444,
1238, 1166 cmꢂ1
;
1H NMR (300 MHz, CDCl3): d 7.99 (d, J = 7.7 Hz, 1H), 7.87–
7.62 (m, 6H), 7.46–7.31 (m, 6H), 5.93 (s, 1H), 3.62 (s, 3H), 3.30 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 161.8, 152.2, 150.6, 147.2, 141.2, 133.3, 132.4, 131.8, 131.0,
129.6, 128.5, 128.3, 128.0, 127.54, 127.48, 127.0, 126.3, 125.9, 125.6, 125.5,
124.0, 117.4, 116.2, 91.3, 36.2, 29.0, 28.2; MS-ESI: m/z: 421 (M+H), 295; HRMS
calcd for C27H21N2O3: 421.1551, found: 421.1555. 4k: White solid; mp 291–
15. General procedure: A mixture of aldehyde (1.1 mmol), b-naphthol (1.0 mmol),
1,3-dimethylbarbutyric acid (1.0 mmol) and 10 mol % of iodine was mixed in a
10 mL flask. The resulting mixture was stirred in preheated oil bath at 120 °C
for the appropriate time (Table 1). After completion, the mixture was quenched
with 15% solution of sodium thiosulfate and extracted with ethyl acetate
(3 ꢁ 10 mL). The combined organic extracts were dried over anhydrous
Na2SO4, concentrated in vacuo, and purified by column chromatography on
silica gel (Acme, 60–120 mesh, ethyl acetate/n-hexane) to afford the pure
product. In few cases, the products were recrystallized from methanol. Spectral
293 °C; IR (KBr):
m ;
2923, 1709, 1669, 1596, 1516, 1345, 1229, 1177 cmꢂ1 1H
NMR (300 MHz, CDCl3): d 8.07 (d, J = 8.7 Hz, 2H), 7.88 (d, J = 8.9 Hz, 1H), 7.85–
7.60 (m, 2H), 7.51 (d, J = 8.9 Hz, 2H), 7.47–7.43 (m, 2H), 7.40 (d, J = 8.9 Hz, 1H),
5.87 (s, 1H), 3.61 (s, 3H), 3.31 (s, 3H); 13C NMR (75 MHz, CDCl3): d 161.8, 152.4,
150.8, 150.4, 147.1, 146.5, 131.8, 130.5, 130.2, 129.2, 128.7, 127.8, 125.8, 123.7,
123.3, 116.3, 115.7, 90.0, 36.0, 29.1, 28.2; MS (ESI): 416 (M+H). 4l: White solid;
mp 276–280 °C; IR (KBr):
m 2922, 2853, 2230, 1707, 1668, 1598, 1454, 1227,
1176 cmꢂ1
;
1H NMR (300 MHz, CDCl3): d 7.89–7.75 (m, 3H), 7.52–7.43 (m, 6H),
data for the products. 4a: White solid, mp 223–225 °C; IR (KBr):
m 2922, 2853,
7.38 (d, J = 9.1 Hz, 1H), 5.82 (s, 1H), 3.61 (s, 3H), 3.32 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 161.8, 152.4, 150.4, 148.8, 147.2, 132.3, 131.8, 130.5, 130.2, 129.1,
128.7, 127.7, 125.8, 123.4, 118.7, 116.3, 115.8, 110.6, 90.2, 36.2, 29.1, 28.2; MS-
ESI: m/z: 396 (M+H); HRMS calcd for C24H18N3O3: 396.1348, found: 396.1340.
1706, 1667, 1644, 1593, 1486, 1233, 1178 cmꢂ1 1H NMR (300 MHz, CDCl3): d
;
7.91 (d, J = 8.3 Hz, 1H), 7.82–7.76 (m, 2H), 7.48–7.28 (m, 5H), 7.18 (t, J = 7.6 Hz,
2H), 7.11–7.04 (m, 1H), 5.76 (s, 1H), 3.59 (s, 3H), 3.31 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 161.9, 152.2, 150.6, 147.1, 143.8, 131.7, 130.9, 129.5, 129.0,
128.4, 128.2, 127.4, 126.7, 125.4, 123.9, 117.3, 116.2, 91.4, 35.9, 29.0, 28.1; MS-