Novel isocyanide-based three-component reaction: A facile synthesis of substituted 1H-chromeno[2,3-d]pyrimidine-5-carboxamides

Article abstract of DOI:10.1016/j.tet.2013.06.080

A mild and efficient method for the synthesis of 1H-chromeno[2,3-d] pyrimidine-5-carboxamide derivatives via a one-pot, three-component reaction of an isocyanide, barbituric acid, and a salicylaldehyde in the presence of acetic acid in ethanol/water mixture at 75 C is reported. This high atom economy reaction led to the construction of one benzopyran ring, and one amide group in a single synthetic step.

Full text of DOI:10.1016/j.tet.2013.06.080

Accepted Manuscript
Novel Isocyanide-Based Three-Component Reaction: A Facile Synthesis of
Substituted 1H-chromeno[2,3-d]pyrimidine-5-carboxamides
Ebrahim Soleimani, Somayeh Ghorbani
PII:
S0040-4020(13)01039-9
10.1016/j.tet.2013.06.080
TET 24556
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 March 2013
Revised Date: 9 June 2013
Accepted Date: 24 June 2013
Please cite this article as: Soleimani E, Ghorbani S, Novel Isocyanide-Based Three-Component
Reaction: A Facile Synthesis of Substituted 1H-chromeno[2,3-d]pyrimidine-5-carboxamides,
Tetrahedron (2013), doi: 10.1016/j.tet.2013.06.080.
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ACCEPTED MANUSCRIPT
Graphical abstract:
One-Pot Three-Component Synthesis of fully substituted 1H-chromeno[2,3-d]pyrimidine-5-
carboxamide derivatives
Ebrahim Soleimani,* and Somayeh Ghorbani
Department of Chemistry, Razi University, Kermanshah 67149-67346, Iran.
R2
O
NH
O
O
CHO
NH
AcOH
EtOH/H2O, 75oC
HN
NH
R1
R1
+ R2
N C
+
O
N
H
O
OH
O
O
12

ACCEPTED MANUSCRIPT
Novel Isocyanide-Based Three-Component Reaction: A Facile Synthesis of Substituted 1H-
chromeno[2,3-d]pyrimidine-5-carboxamides
Ebrahim Soleimani, and Somayeh Ghorbani
Department of Chemistry, Razi University, Kermanshah 67149-67346, Iran.
Abstract
A mild and efficient method for the synthesis of 1H-chromeno[2,3-d]pyrimidine-5-carboxamide derivatives
via a one-pot, three-component reaction of an isocyanide, barbituric acid and a salicylaldehyde in the
presence of acetic acid in ethanol/water mixture at 75 ˚C is reported. This high atom economy reaction led
to the construction of one benzopyran ring, and one amide group in a single synthetic step.
Keywords: Chromeno[2,3-d]pyrimidine, Multi-component reactions, Benzopyran, Salicylaldehyde,
Barbituric acid, Isocyanide.
1. Introduction
Multicomponent reactions (MCRs), because of their productivity, simple procedures, time-saving
manner, convergence, and facile execution, are one of the best tools in combinatorial chemistry.1 MCRs,
particularly those performed in aqueous media, have become increasingly useful tools for the synthesis of
chemically and biologically important compounds because of their environmentally friendly atom economy
and green characteristics.1 The ability of isocyanide to undergo facile α-addition with a nucleophile and an
electrophile under mild conditions made it a popular reactant for the development of novel MCRs.2 As a
result of this orthogonal reactivity, MCRs that involve isocyanides are considered as powerful tools in
modern organic synthesis as well as in the field of combinatorial chemistry and drug discovery.3 Therefore,
the design of novel isocyanide-based multicomponent reactions (IMCRs) can be considered as an
interesting research topic that also satisfies the practical interest of applied science.4 As a result, the number
of new IMCRs reported in recent years has grown rapidly.5
Corresponding author. Fax: +98-831-4274559; e-mail: e_soleimanirazi@yahoo.com
1

ACCEPTED MANUSCRIPT
The benzopyrano[2,3-d]pyrimidines are organic compounds which are constructed from two fused
benzopyran and pyrimidine rings which exhibit extremely diverse biological and pharmaceutical
activities.6-17 The benzopyrans (4H-chromene) have shown a wide range of biological activities such as anti
HBV, cytotoxic,6 antibacterial,7 antioxidant,8 antigenotoxic,9 ATP sensitive potassium channel openers10
and antiangiogenic activity [11]. 11 On the other hand, a pyrimidine scaffold is the base of many bioactive
molecules such as antitubercular,12 antibacterial,13 antitumor,14 antiinflammatory,15 antifungal16 and
antileishmanial agent.17 Consequently, synthetic methodologies for the synthesis of novel benzopyrano[2,3-
d]pyrimidine18 are of particular interests to organic and medicinal chemists.
2. Results and discussion
Due to the aforementioned reasons, and as a part of our ongoing research on isocyanide-based MCRs,5
we report herein the synthesis of 1H-chromeno[2,3-d]pyrimidine-5-carboxamide derivatives 4 through a
one-pot, three-component condensation of the salicylaldehydes 1, barbituric acid 2, and isocyanides 3 in the
presence of acetic acid in ethanol/water mixture (4:1) at 75 ˚C (Scheme 1).
R2
O
NH
O
O
CHO
NH
AcOH
EtOH/H2O, 75oC
HN
NH
R1
R1
+
+ R2
N C
O
N
H
O
OH
O
O
4
1
2
3
Scheme 1. Synthesis of 1H-chromeno[2,3-d]pyrimidine-5-carboxamide
We chose the reaction of salicylaldehyde, barbituric acid, and cyclohexyl isocyanide as a model system for
the optimization study. First, we compared the reaction rate in different solvents by measuring the isolated
yield using identical amounts of reactants and catalyst for a fixed reaction time of 24 h at 75 ˚C (entries 1-
7). The desired products were scarcely obtained in non-polar solvents and even ethanol or water as a polar
protic solvent failed to produce the desired product in high (>80%) yield. It was found that addition of
water to the ethanol solution can improve the reaction outcome and interestingly (entries 8-12) when the
reaction was performed in ethanol /water mixture (4:1) the corresponding product was obtained
qualitatively (entry 12). This effect can be explained by a simple acid-catalysis mechanism facilitated by
2

ACCEPTED MANUSCRIPT
the strong hydrogen bond interaction at the organic–water interface which stabilizes the reaction
intermediate. Next, we studied the model reaction in ethanol/water at different temperatures (entries 13-15).
The reaction rate increased as the temperature was raised. At 75 ˚C, the maximum yield (99%) was
obtained in a reaction time of 24 h (entry 13). Also, the model reaction was studied in ethanol/water (4:1) at
75 ˚C using different amounts of acetic acid (entries 17-19). The best results were obtained with 100 mol %
of acetic acid. Further work indicated that the best results were obtained when the reaction was carried out
at 75 °C for 24 h in ethanol/water (4:1) using 100 mol % of acetic acid (entry 13).
Table 1: Optimization of the reaction
O
NH
O
O
CHO
NH
HN
NH
24 h
+
+
N
C
Temp.
OH
O
N
H
O
O
O
1
2
3
4
Entry
1
Solvent
Water
Ethanol
Temperature Acetic acid (%) Yield (%)
75
75
75
75
75
75
25
75
75
75
75
75
75
50
25
75
75
75
75
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
10
71
78
72
32
44
trace
trace
85
83
87
93
99
93
73
51
59
67
79
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Methanol
Ethyl acetate
Acetonitrile
Toluene
Dichloromethane
Water/ Ethanol (1:1)
Water/ Ethanol (2:1)
Water/ Ethanol (1:2)
Water/ Ethanol (1:3)
Water/ Ethanol (1:4)
Water/ Ethanol (1:4)
Water/ Ethanol (1:4)
Water/ Ethanol (1:4)
Water/ Ethanol (1:4)
Water/ Ethanol (1:4)
Water/ Ethanol (1:4)
Water/ Ethanol (1:4)
25
50
75
86
3

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With the optimized condition established above, we next attempted to extend the process to two different
isocyanides such as 1,1,3,3-tetramethylbutyl isocyanide and cyclohexyl isocyanide, and various types of
salicylaldehydes 1 such as salicylaldehyde, 3-methoxysalicylaldehyde, 4-hydroxysalicylaldehyde, 5-
methylsalicylaldehyde and 5-nitrosalicylaldehyde. The results in Table 2 show that all reactions proceeded
smoothly to afford the expected 1H-chromeno[2,3-d]pyrimidine-5-carboxamide derivatives in good to
1
excellent yields. The structure of the products was deduced from their mass, H NMR, and 13C NMR
spectra (see the experimental section).
Table 2. Synthesis of 1H-chromeno[2,3-d]pyrimidine-5-carboxamide derivatives.
O
NH
O
NH
O
NH
O
NH
O
O
O
O
O2N
NH
NH
NH
NH
O
N
H
O
O
N
H
O
O
N
H
O
HO
O
N
H
O
4a
4c
4d
OMe
4b
O
NH
O
NH
O
NH
O
O
O
Me
NH
NH
O
NH
O
4g
N
H
O
O
N
H
O
N
H
O
4f
OMe
4e
Entry
R1
H
R2
Product
4a
Yield (%)
1
2
3
4
5
6
7
1,1,3,3,-Tetramethylbutyl
95
95
97
60
99
90
99
4- HO
1,1,3,3,-Tetramethylbutyl
4b
3- CH3O
5- O2N
H
1,1,3,3,-Tetramethylbutyl
4c
1,1,3,3,-Tetramethylbutyl
4d
Cy
Cy
Cy
4e
5- H3C
4f
3- CH3O
4g
aReaction condition: salicylaldehydes 1 (1 mmol), barbituric acid 2 (1 mmol), and isocyanides 3 (1 mmol),
b
and AcOH (1 mmol) in ethanol/water (4:1) (5 mL) stirred at 75 ˚C for 24 h. Isolated yield.
4

ACCEPTED MANUSCRIPT
Mechanistically, it is conceivable that the reaction involves the initial formation of the activated alkene,
(benzopyran ring) 5 through a Knoevenagel condensation of salicylaldehydes 1 and barbituric acid 2.19
Benzopyran ring 5 undergoes nucleophilic addition with the isocyanide 3 followed by nucleophilic attack
on the isocyanide by the water to afford 1H-chromeno[2,3-d]pyrimidine-5-carboxamide derivatives 4. To
clarify the proposed mechanism, first, the benzopyran ring 5 was synthesized according to previous work,19
by means of reaction between salicylaldehydes 1 and barbituric acid 2. Next, the reaction of the benzopyran
ring 5 with the isocyanide in ethanol/water mixture in the presence of acetic acid afforded the
corresponding 1H-chromeno[2,3-d]pyrimidine-5-carboxamide derivatives 4.
R2
R2
N
C
N
H2O
C
3
O
N
O
O
CHO
OH
NH
NH
HN
NH
+
O
O
O
N
H
O
O
O
1
2
5
6
R2
NH
O
O
NH
O
N
H
O
4
Scheme 2. Proposed mechanism
During our investigation, we tried to use the malononitrile instead of barbituric acid. For this, we
examined the reaction of malononitrile, and salicylaldehydes with isocyanide in the presence of a acetic
acid in ethanol/water (4:1) at 75 ˚C for 24 h. We found that isocyanide was not involved in the reaction, and
consequently, the expected product 2-amino-3-cyano-N-cyclohexyl-4H-chromene-4-carboxamide 8 was
not obtained. Isolation and characterization of the resulted product showed that under these conditions, the
reaction afforded 2-imino-2H-chromene-3-carbonitrile 7 instead, which was reported by was reported by
Proenca et al.20 (Scheme 3).
5

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CN
NH
O
8
CHO
NC
NC
AcOH
EtOH/H2O, 75oC
+
+
N C
OH
O
NH
CN
O
NH2
7
Scheme 3.
3. Conclusion
In conclusion, we have developed a new isocyanide based multicomponent reaction for the synthesis of
a wide range of 1H-chromeno[2,3-d]pyrimidine-5-carboxamides from salicylaldehydes and barbituric acid
and isocyanides. This high yielding reaction has been shown to display a good functional group tolerance,
while the product isolation is very straightforward. We hope that this approach may be of value to others
seeking novel synthetic fragments with unique properties for medicinal chemistry programs.
4. Experimental Section:
4.1. General procedure for synthesis of 1H-chromeno[2,3-d]pyrimidine-5-carboxamide derivatives (4a-g)
A solution of salicylaldehydes (1 mmol), barbituric acid (1 mmol), isocyanide (1 mmol) and AcOH (1
mmol) in ethanol/water (4:1) (5 mL) were stirred for 24 h at 75 ˚C. After completion of the reaction, as
indicated by TLC, the solvent was removed under vacuum and the solid residue was washed with
ethanol/water mixture (1:1). Then the solid residue was crystallized from ethanol to afford products as
colourless crystals.
4.2.
2,3,4,5-Tetrahydro-N-(2,4,4-trimethylpentan-2-yl)-2,4-dioxo-1H-chromeno[2,3-d]pyrimidine-5-
carboxamide (4a)
White powder (0.35 g, yield 95%); mp 293-295 °C. IR (KBr) (νmax/cm-1): 3300, 2954, 1694, 1651, 1531,
1488. MS, m/z: 372 (M++1), 216, 202, 172, 129, 83, 69, 57. 1H NMR (250 MHz, DSMO-d6): δH (ppm) 0.91
6

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2
2
(9H, s, C(CH3)3), 1.22, 1.27 (6H, 2s, CH3-C-CH3), 1.53 (1H, d, JHH = 12.5 Hz, CH2), 1.64 (1H, d, JHH
=
12.5 Hz, CH2), 4.55 (1H, s, CH), 7.12-7.49 (4H, m, H-Ar), 7.78, 11.05, 11.91 (3H, 3s, 3NH). 13C NMR (63
MHz, DSMO-d6): δC (ppm) 28.7 (CH3-C-CH3), 28.9 (C(CH3)3), 31.0 (C(CH3)3), 31.1 (CH2), 50.2 (CH3-C-
CH3), 54.1 (CH), 85.5, 116.2, 120.5, 124.9, 128.5, 128.8, 149.0, 149.6 (O-C=C and 6C-Ar), 155.0, 169.6,
171.0 (3C=O). Anal. Calcd for C20H25N3O4: C, 64.67; H, 6.78; N, 11.31. Found: C, 64.73; H, 6.69; N,
11.33.
4.3.
2,3,4,5-Tetrahydro-8-hydroxy-N-(2,4,4-trimethylpentan-2-yl)-2,4-dioxo-1H-chromeno[2,3-
d]pyrimidine-5-carboxamide (4b)
White powder (0.37 g, yield 95%); mp 336-339 °C. IR (KBr) (νmax/cm-1): 3610, 3300, 2953, 1695, 1661,
1
1544, 1473. MS, m/z: 388 (M++1), 332, 246, 187, 129, 110, 69, 57. H NMR (250 MHz, DSMO-d6): δH
(ppm) 0.91 (9H, s, C(CH3)3), 1.23, 1.27 (6H, 2s, CH3-C-CH3), 1.60 (1H, d, 2JHH = 14.0 Hz, CH2), 1.70 (1H,
d, 2JHH = 14.0 Hz, CH2), 4.41 (1H, s, CH), 6.47 (1H, s, H-Ar), 6.62 (1H, d, 3JHH = 7.5 Hz, H-Ar), 7.26 (1H,
3
d, JHH = 7.5 Hz, H-Ar), 7.70 (1H, s, OH), 9.84, 11.03, 11.84 (3H, 3s, 3NH). 13C NMR (63 MHz, DSMO-
d6): δC (ppm) 28.7 (CH3-C-CH3), 28.9 (C(CH3)3), 30.9 (C(CH3)3), 31.1 (CH2), 50.2 (CH3-C-CH3), 54.1
(CH), 85.8, 102.5, 110.6, 112.4, 129.4, 149.0, 149.6, 154.6 (O-C=C and 6C-Ar), 157.3, 163.5, 170.1
(3C=O). Anal. Calcd for C20H25N3O5: C, 62.00; H, 6.50; N, 10.85. Found: C, 62.01; H, 6.42; N, 10.83.
4.4.
2,3,4,5-Tetrahydro-9-methoxy-N-(2,4,4-trimethylpentan-2-yl)-2,4-dioxo-1H-chromeno[2,3-
d]pyrimidine-5-carboxamide (4c)
White powder (0.39 g, yield 97%); mp 360-362 °C. IR (KBr) (νmax/cm-1): 3311, 2959, 1699, 1645, 1532,
1470. MS, m/z: 402 (M+), 368, 330, 246, 187, 69, 57. 1H NMR (250 MHz, DSMO-d6): δH (ppm) 0.90 (9H,
2
2
s, C(CH3)3), 1.21, 1.26 (6H, 2s, CH3-C-CH3), 1.58 (1H, d, JHH = 12.5 Hz, CH2), 1.70 (1H, d, JHH = 14.0
Hz, CH2), 3.84 (1H, s, OCH3), 4.53 (1H, s, CH), 7.00-7.12 (3H, m, H-Ar), 7.72, 11.02, 11.92 (3H, 3s,
3NH). 13C NMR (63 MHz, DSMO-d6): δC (ppm) 28.7 (CH3-C-CH3), 28.9 (C(CH3)3), 31.0 (C(CH3)3), 31.1
(CH2), 50.2 (CH3-C-CH3), 54.1 (CH), 55.66 (OCH3), 85.5, 111.3, 119.8, 121.4, 124.6, 138.0, 147.3, 149.5
(O-C=C and 6C-Ar), 154.6, 163.4, 169.7 (3C=O). Anal. Calcd for C21H27N3O5: C, 62.83; H, 6.78; N, 10.47.
Found: C, 62.82; H, 6.75; N, 10.49.
7

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4.5. 2,3,4,5-Tetrahydro-N-(2,4,4-trimethylpentan-2-yl)-7-nitro-2,4-dioxo-1H-chromeno[2,3-d]pyrimidine-
5-carboxamide (4d)
White powder (0.25 g, yield 60%); mp 360-362 °C. IR (KBr) (νmax/cm-1): 3307, 2981, 1690, 1655, 1566,
1489. MS, m/z: 417 (M+), 370, 261, 217, 97, 83, 57. 1H NMR (250 MHz, DSMO-d6): δH (ppm) 0.98 (9H, s,
C(CH3)3), 1.31 (6H, s, CH3-C-CH3), 1.56 (2H, s, CH2), 4.91 (1H, s, CH), 6.70-8.00 (3H, m, H-Ar), 8.04,
8.15, 9.72 (3H, 3s, 3NH). 13C NMR (63 MHz, DSMO-d6): δC (ppm) 26.6 (CH3-C-CH3), 26.7 (C(CH3)3),
30.8 (C(CH3)3), 30.9 (CH2), 51.9 (CH3-C-CH3), 54.9 (CH), 80.0, 117.1, 117.6, 123.8, 125.1, 128.5, 137.6,
151.3 (O-C=C and 6C-Ar), 164.5, 165.0, 173.0 (3C=O). Anal. Calcd for C20H24N4O6: C, 57.68; H, 5.81; N,
13.45. Found: C, 57.73; H, 5.82; N, 13.51.
4.6. N-Cyclohexyl-2,3,4,5-tetrahydro-2,4-dioxo-1H-chromeno[2,3-d]pyrimidine-5-carboxamide (4e)
White powder (0.34 g, yield 99%); mp 340-342 °C. IR (KBr) (νmax/cm-1): 3300, 2963, 2850, 1694, 1539,
1
1489. MS, m/z: 342 (M++1), 216, 172, 145, 116, 83, 63, 55. H NMR (300 MHz, DSMO-d6): δH (ppm)
1.16-1.70 (10H, m, 5CH2 of cyclohexyl), 3.40 (1H, m, CH-NH of cyclohexyl), 4.48 (1H, s, CH), 7.08-7.45
3
13
(4H, m, H-Ar), 8.21 (1H, d, JHH = 7.8 Hz, CH-NH of cyclohexyl), 11.04, 11.90 (2H, 2s, 2NH). C NMR
(63 MHz, DSMO-d6): δC (ppm) 24.3, 25.1, 32.1 (C-cyclohexyl), 47.7 (CH-NH), 50.8 (CH), 83.3, 116.3,
120.3, 128.4, 128.7, 148.3, 149.6, 154.4 (O-C=C and 6C-Ar), 159.7, 163.4, 170.0 (3C=O). Anal. Calcd for
C18H19N3O4: C, 63.33; H, 5.61; N, 12.31. Found: C, 63.34; H, 5.53; N, 12.33.
4.7. N-Cyclohexyl-2,3,4,5-tetrahydro-7-methyl-2,4-dioxo-1H-chromeno[2,3-d]pyrimidine-5-carboxamide
(4f)
White powder (0.32 g, yield 90%); mp 333-336 °C. IR (KBr) (νmax/cm-1): 3300, 2934, 2850, 1690, 1618,
1
1539, 1488. MS, m/z: 356 (M++1), 230, 186, 116, 83, 63, 55. H NMR (250 MHz, DSMO-d6): δH (ppm)
1.22-1.68 (10H, m, 5CH2 of cyclohexyl), 3.40 (1H, m, CH-NH of cyclohexyl), 2.26 (3H, s, CH3), 4.43 (1H,
s, CH), 7.01-7.24 (4H, m, H-Ar), 8.17, 11.03, 11.93 (3H, 3s, 3NH). 13C NMR (63 MHz, DSMO-d6): δC
(ppm) 21.2 (CH3), 24.3, 25.0, 32.5 (C-cyclohexyl), 43.7 (CH-NH), 47.5 (CH), 85.0, 116.0, 120.0, 128.0,
129.0, 144.5, 147.0, 154.0 (O-C=C and 6C-Ar), 159.0, 165.0, 170.0 (3C=O). Anal. Calcd for C19H21N3O4:
C, 64.21; H, 5.96; N, 11.82. Found: C, 64.22; H, 5.91; N, 11.79.
8

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4.8. N-cyclohexyl-2,3,4,5-tetrahydro-9-methoxy-2,4-dioxo-1H-chromeno[2,3-d]pyrimidine-5-carboxamide
(4g)
White powder (0.37 g, yield 99%); mp 332-334 °C. IR (KBr) (νmax/cm-1): 3301, 2943, 2825, 1691, 1533
1
1488. MS, m/z: 372 (M++1), 246, 202, 126, 83, 63, 55. H NMR (300 MHz, DSMO-d6): δH (ppm) 1.23-
1.88 (10H, m, 5CH2 of cyclohexyl), 3.79 (1H, m, CH-NH of cyclohexyl), 3.83 (3H, s, OCH3), 4.48 (1H, s,
CH), 6.81-7.13 (3H, m, H-Ar), 8.20, 10.66, 11.00 (3H, 3s, 3NH). 13C NMR (75 MHz, DSMO-d6): δC (ppm)
23.7, 24.4, 25.1, 30.2, 32.1 (C-cyclohexyl), 47.7 (CH-NH), 49.2 (CH), 55.7 (OCH3), 84.8, 111.2, 119.3,
121.1, 124.8, 138.75, 147.3, 149.6 (O-C=C and 6C-Ar), 155.0, 163.5, 169.8 (3C=O). Anal. Calcd for
C19H21N3O5: C, 61.45; H, 5.70; N, 11.31. Found: C, 61.43; H, 5.71; N, 11.24.
Acknowledgements
We gratefully acknowledge financial support from the Iran National Science Foundation (INSF) and
Research Council of Razi University.
References and notes
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Soleimani, E.; Khodaei, M. M.; Batooie, N.; Baghbanzadeh, M. Green Chem. 2011, 13, 566-569
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Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101-4111. (f) Jacobi von Wangelin, A.;
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