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Catalyst-Free One-Pot Three-Component Synthesis of Diversely Substituted 5‑Aryl-2-oxo-/thioxo-2,3dihydro‑1H‑benzo[6,7]chromeno[2,3‑d]pyrimidine-4,6,11(5H)‑triones Under Ambient Conditions Goutam Brahmachari* and Nayana Nayek Laboratory of Natural Products & Organic Synthesis, Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731 235, West Bengal, India S Supporting Information *
ABSTRACT: A simple, catalyst-free, straightforward, and highly efficient one-pot synthesis of pharmaceutically interesting diverse kind of a new series of functionalized 5-aryl-2-oxo-/ thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-triones 4 (4-1−4-37) and substituted 5,5′-(1,4-phenylene)bis(2-oxo-/thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione) derivatives 4′ (4′-1−4′-3) has been developed based on a threecomponent reaction between barbituric acid/N,N-dimethylbarbituric acid/2-thiobarbituric acid (1), aromatic aldehydes (2), and 2-hydroxy-1,4-naphthoquinone (3) in aqueous ethanol at room temperature (25−30 °C). The salient features of this protocol are mild reaction conditions, use of no catalyst, no need of column chromatographic purification, excellent yields, high atom economy, eco-friendliness, easy isolation of products, and reusability of reaction media.
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marin,21 and many more under varying reaction conditions, involving the use of catalysts and additives, organic solvents, heating/refluxing, microwaves, electrolysis, and so forth.22 Again, chromenes and related O-heterocyclic derivatives are a group of biologically promising molecular frameworks commonly found in natural and synthetic bioactive compounds exhibiting a broad spectrum of biological activities.23 In addition to these two N- and O-heterocyclic scaffolds, 2hydroxy-1,4-naphthoquinone (known as lawsone), a major chemical constituent of the medicinal plant Lawsonia inermis Linn., has been evaluated to possess many interesting biological and pharmacological activities so far, which motivated our group to explore this useful scaffold in synthesizing a series of novel bislawsone compounds with potent anticancer activity.24,25 However, available reports on the novel scaffold developments with lawsone are still very limited. Currently, molecular hybridization (MH)26 is well-practiced in the process of rational drug design based on the recognition of pharmacophoric subunits in the molecular structure of two or more known bioactive derivatives which, through an adequate fusion of these subunits, leads to the design of new hybrid architectures with extended pharmacological potential.27 Considering the success of MH techniques toward the design of various lead candidates coupled with the proven pharmaceutical potential of barbiturate/thiobarbiturate deriva-
INTRODUCTION Heterocyclic moieties are widely prevalent in bioactive natural products as well as in the marketed pharmaceuticals, agrochemicals, dyes, and many other application-oriented materials.1−5 Polyfunctionalized heterocycles, very particularly, occupy a dominating position in the drug discovery process, and recently, it has been estimated that approximately more than 70% of all enlisted pharmaceuticals and agrochemicals bear at least one heterocyclic ring.6 Hence, research on the synthesis of polyfunctionalized heterocyclic compounds has gained special attention. Among N-heterocycles, pyrimidine and its derivatives have been studied for over a century because of their varying chemical and biological significance;7,8 a good number of such heterocyclic scaffolds are reported for a wide range of biological profiles including antioxidant, antiinflammatory, immunomodulating, antibacterial, antiviral, and antitumor activity.9−11 Categorically, barbituric/2-thiobarbituric acids, an important class of pharmaceutically promising pyrimidine derivatives, find potential applications as building blocks for a series of barbiturate/thiobarbiturate drugs used as hypnotics, sedatives, anticonvulsants, anesthetics, antioxidants, antifungal, and central nervous system depressants.12−14 Combination of barbituric/thiobarbituric acid moieties with other pharmacophoric groups, thus, may offer a possibility to synthesize numerous new types of other scaffolds with desired potential biological effects. With this view, a large number of endeavors were undertaken previously in fusing this important scaffold with other diverse molecular skeletons such as 1,3diketones,15,16 isatins,17−19 Meldrum’s acid,20 4-hydroxycou© 2017 American Chemical Society
Received: June 15, 2017 Accepted: August 14, 2017 Published: August 28, 2017 5025
DOI: 10.1021/acsomega.7b00791 ACS Omega 2017, 2, 5025−5035
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Scheme 1. Catalyst-Free One-Pot Room-Temperature Synthesis of Diversely Functionalized 5-Aryl-2-oxo-/thioxo-2,3-dihydro1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-triones (4)
Table 1. Optimization of Reaction Conditions for the Synthesis of 5-Aryl-2-oxo-/thioxo-2,3-dihydro-1Hbenzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-triones (4)
entry
solvent
time (h)
yield (%)a,b
1 2 3 4 5 6
H2O EtOH EtOH/H2O (1:1 v/v) EtOH/H2O (2:1 v/v) EtOH/H2O (1:2 v/v) neat
20 20 12 20 20 20
61 72 99 81 68 trace
a
Reaction Conditions: barbituric acid (0.5 mmol), benzaldehyde (0.5 mmol), and 2-hydroxy-1,4-naphthoquinone (0.5 mmol) in 4 mL of water/ ethanol/ethanol−water/neat at room temperature (25−30 °C) without any added catalyst. bIsolated yields.
already proved itself as a greener solvent for organic syntheses and an alternative to toxic organic solvents because of its solvation with most type of media and low toxicity.47,48 Therefore, the combination of water and ethanol is receiving considerable attention as an important green solvent system in organic transformations with green procedure.49−55 Hence, the development of new synthesis methods keeping in view of all such recent trends has become a new research direction, which enables the simultaneous growth of both MCRs and green solvent systems toward ideal organic synthesis in drug discovery and materials science. As part of our ongoing research in the field of green synthesis,56−68 we herein wish to report a convenient, clean, facile, and catalyst-free practical method for the synthesis of a new series of functionalized 5aryl-2-oxo-/thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3d]pyrimidine-4,6,11(5H)-triones (4) from the one-pot MCR between barbituric acid/N,N-dimethylbarbituric acid/2-thiobarbituric acid (1), aromatic aldehydes (2), and 2-hydroxy-1,4naphthoquinone (3) in aqueous ethanol at ambient conditions (25−30 °C); the overall results are summarized in Scheme 1. The key advantages of this newly developed protocol are the clean reaction profile, use of no catalyst and no toxic organic solvents, mild reaction conditions at room temperature, energy efficiency, use of commercially available low-cost starting materials, no need of column chromatographic purification, high atom economy (89.43−93.01%), and excellent yields.
tives, functionalized chromenes, and 2-hydroxy-1,4-naphthoquinone (lawsone)-derived compounds, we felt excitement whether all of these privileged scaffolds could be bound together within one molecular framework so as to construct a novel series of polyfunctionalized heterocyclic architectures by designing an efficient protocol that would, at the same time, satisfy several green chemistry aspects. It has been a major challenge of modern drug discovery, indeed, to design highly efficient chemical reaction sequences that provide maximum structural complexity and diversity with a minimum number of synthetic steps to assemble compounds with interesting properties,28,29 and multicomponent reactions (MCRs) have recently been proven to be an efficient and green method for the synthesis of structurally diverse and complex organic compounds from simple starting materials under one-pot condition with huge benefits, particularly in regard to a facile automation, operational simplicity, and reduction in the number of workup steps, thereby minimizing the extraction and purification processes as well as waste generation and saving energy and manpower.30−38 In addition, designing for room-temperature conditions coupled with other green aspects is also an area of current choice in synthetic organic chemistry.39 From green chemistry perspective, water is considered as a safe and uniquely redox-stable green solvent which facilitates typical solvation and molecular assembly processes, leading to the remarkable modes of reactivity and selectivity of a wide variety of organic reactions.40−46 Apart from water, ethanol also 5026
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Table 2. Synthesis of Diversely Substituted 5-Aryl-2-oxo-/thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine4,6,11(5H)-triones (4)
melting point (°C) 1
2
entry
substituent (R )
substituent (X)
substituent (R )
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
H H H H H H H H H H H H CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 H H H H H H H H H H H H
O O O O O O O O O O O O O O O O O O O O O O O O O S S S S S S S S S S S S
C6H5 4-CH3C6H4 4-OCH3C6H4 4-CF3C6H4 4-CNC6H4 3-BrC6H4 3-NO2C6H4 4-NO2C6H4 2,5-di-OCH3C6H3 3,4,5-tri-OCH3C6H2 3-CHOC6H4 4-CHOC6H4 C6H5 4-CH3C6H4 4-OCH3C6H4 4-CF3C6H4 4-CNC6H4 3-BrC6H4 4-BrC6H4 3-NO2C6H4 4-NO2C6H4 2,5-di-OCH3C6H3 3,4-OCH2OC6H3 3-CHOC6H4 4-CHOC6H4 C6H5 4-OCH3C6H4 4-CF3C6H4 4-CNC6H4 3-BrC6H4 3-NO2C6H4 4-NO2C6H4 2,5-di-OCH3C6H3 3,4,5-tri-OCH3C6H2 3-CHOC6H4 4-CHOC6H4 2-furyl
product 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4
(4-1) (4-2) (4-3) (4-4) (4-5) (4-6) (4-7) (4-8) (4-9) (4-10) (4-11) (4-12) (4-13) (4-14) (4-15) (4-16) (4-17) (4-18) (4-19) (4-20) (4-21) (4-22) (4-23) (4-24) (4-25) (4-26) (4-27) (4-28) (4-29) (4-30) (4-31) (4-32) (4-33) (4-34) (4-35) (4-36) (4-37)
time (h) 12 12 16 12 14 16 14 13 20 16 18 17 16 18 20 12 14 16 15 16 15 20 21 19 18 20 22 16 18 18 18 18 22 20 22 21 22
yield (%) 99 98 97 96 92 97 97 99 98 98 99 99 97 96 95 98 98 99 99 98 98 97 98 99 98 96 97 95 97 98 91 92 87 93 93 93 96
a,b
found
reported
198−200 102−105 140−141 188−190 192−194 162−165 165−167 176−178 198−200 209−210 189−191 191−192 152−154 182−184 160−162 158−160 188−190 209−210 178−181 206−208 178−180 130−132 178−179 180−182 198−200 164−165 174−176 168−170 172−174 193−195 188−190 168−170 180−182 198−200 184−186 192−194 162−166
a Reaction Conditions: barbituric acids (1; 0.5 mmol), aldehydes (2; 0.5 mmol), and 2-hydroxy-1,4-naphthoquinone (3; 0.5 mmol) in 4 mL of aqueous ethanol (1:1 v/v) at room temperature (25−30 °C) in the absence of any catalyst. bIsolated yields.
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RESULTS AND DISCUSSION On the basis of the critical survey of the literature on catalystfree organic transformations coupled with our own experience in performing this kind of organic synthesis,69 we envisioned that such a 1H-benzo[6,7]chromeno[2,3-d]pyrimidine scaffold might be constructed out of a one-pot MCR of its starting constituents such as barbituric acid, aldehyde, and 2-hydroxy1,4-naphthoquinone without the aid of any catalyst in the presence of a suitable solvent. First, we checked our model reaction between barbituric acid (1-1; 1 equiv), benzaldehyde (2-1; 1 equiv), and 2-hydroxy-1,4-naphthoquinone (3; 1 equiv)
in the absence of any catalyst in aqueous medium under ambient conditions, thereby isolating the desired compound, 5phenyl-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone (4-1), in 61% yield at 20 h (Table 1, entry 1). Then, we performed the same reaction several times using either ethanol or ethanol−water mixtures in varying proportions (v/v) as solvents or no solvent at ambient conditions and observed that the reaction took place smoothly in aqueous ethanol (1:1 v/v), affording the desired product 4-1 in 99% yield at 12 h (Table 1, entry 3). Compound 4-1 was 5027
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Table 3. Synthesis of Substituted 5,5′-(1,4-Phenylene)bis(2-oxo-/thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3d]pyrimidine-4,6,11(5H)-trione) Derivatives 4′ (4′-1−4′-3)
melting point (°C) 1
entry
substituent (R )
substituent (X)
product
time (h)
1 2 3
H CH3 H
O O S
4′ (4′-1) 4′ (4′-2) 4′ (4′-3)
18 22 20
yield (%) 98 92 94
a,b
found
reported
199−200 195−203 250−252
a
Reaction conditions: barbituric acids (1; 1.0 mmol), terephthalaldehyde (2; 0.5 mmol), and 2-hydroxy-1,4-naphthoquinone (3; 1.0 mmol) in 5 mL of aqueous ethanol (1:1 v/v) at room temperature (25−30 °C) in the absence of any catalyst. bIsolated yields.
aryl-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone derivatives (4-16−4-25) (Table 2, entries 16−25) from the one-pot reaction of N,N-dimethylbarbituric acid (1; 1 equiv) with a variety of functionalized aromatic aldehydes (2; 1 equiv) and 2-hydroxy-1,4-naphthoquinone (3; 1 equiv) using identical reaction conditions; all of them underwent the reaction in a facile manner, affording the desired products 4-16−4-25 (Table 2, entries 16−25) with excellent yields ranging from 97 to 99% within 12−21 h. However, aliphatic aldehydes were found reluctant to undergo the reaction; we observed that both butyraldehyde and isobutyraldehyde upon treating separately with the mixture of 2hydroxy-1,4-naphthoquinone and barbituric acid/N,N-dimethylbarbituric acid under the identical reaction conditions produced only the desired products with 23−28% yield. Encouraged by these results, we then planned to replace barbituric acid/N,N-dimethylbarbituric acid with 2-thiobarbituric acid so as to further extend the newly developed protocol in generating 2-thioxo-substituted analogues. For this purpose, we performed the reaction between 2-thiobarbituric acid (1-26; 1 equiv), benzaldehyde (2-26; 1 equiv), and 2-hydroxy-1,4naphthoquinone (3; 1 equiv) in aqueous ethanol (1:1 v/v) under the same reaction conditions, and we were delighted to have the desired product, 5-phenyl-2-thioxo-2,3-dihydro-1Hbenzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione (426) (Table 2, entry 26), in 96% yield at 20 h. We, furthermore, utilized the optimized reaction conditions to synthesize a series of new 5-aryl-2-thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione derivatives (4-27−4-36) (Table 2, entries 27−36) from the one-pot reaction of 2thiobarbituric acid (1; 1 equiv) with a varying range of aromatic aldehydes (2; 1 equiv) containing different functionalities such as bromo, cyano, formyl, mono-, di-, and trimethoxyls, nitro, trifluoromethyl, and so forth as substituents and 2-hydroxy-1,4naphthoquinone (3; 1 equiv) in aqueous ethanol (1:1 v/v) without the aid of any catalyst under ambient conditions. All reactions were successfully completed, furnishing the expected products 4-27−4-36 (Table 2, entries 27−36) with excellent yields ranging from 87 to 98% within 16−22 h. In addition, a
characterized by its analytical and spectral properties. The overall results are summarized in Table 1. Under the optimized conditions, we then carried out the reaction between barbituric acid, 4-methylbenzaldehyde, and 2hydroxy-1,4-naphthoquinone and another reaction between barbituric acid, 4-methoxybenzaldehyde, and 2-hydroxy-1,4naphthoquinone; both the reactions furnished the respective desired products, viz., 5-(p-tolyl)-1H-benzo[6,7]chromeno[2,3d]pyrimidine-2,4,6,11(3H,5H)-tetraone (4-2) (Table 2, entry 2) and 5-(4-methoxyphenyl)-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone (4-3) (Table 2, entry 3), in 98 and 97% yield, respectively, within 12−16 h. To check the generality as well as the effectiveness of this newly developed protocol, a number of aromatic aldehydes with varying functionalities such as bromo, cyano, formyl, di- and trimethoxyls, and nitro were reacted with barbituric acid and 2-hydroxy-1,4-naphthoquinone using identical reaction conditions; all of these nine entries underwent the reaction smoothly, affording the corresponding 5-aryl-2-oxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-triones (4-4−4-12) (Table 2, entries 4−12) in excellent yields ranging from 92 to 99% at room temperature within 12−20 h. Inspired by these results, we then replaced unsubstituted barbituric acid with N,N-dimethylbarbituric acid and carried out a similar set of three different reactions from the mixture of this substituted barbituric acid (1 equiv) and 2-hydroxy-1,4naphthoquinone (1 equiv), separately treating with benzaldehyde (1 equiv), 4-methylbenzaldehyde (1 equiv), and 4methoxybenzaldehyde (1 equiv) in aqueous ethanol (1:1 v/v) under the catalyst-free conditions just at room temperature. To our delight, all three reactions produced the expected products, 1,3-dimethyl-5-phenyl-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone (4-13), 1,3-dimethyl-5(p-tolyl)-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone (4-14), and 5-(4-methoxyphenyl)-1,3-dimethyl-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone (4-15), in 97, 96, and 95% yield, respectively, within 16−20 h (Table 2, entries 13−15). We then extended this methodology in synthesizing 11 more new 1,3-dimethyl-55028
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Scheme 2. Proposed Mechanism for the Aqueous Ethanol-Mediated Three-Component One-Pot Synthesis of Functionalized 5Aryl-2-oxo-/thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione 4 at Ambient Conditions
dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine4,6,11(5H)-triones (4) from the three-component reaction of barbituric acids (1), aromatic aldehydes (2), and 2-hydroxy-1,4naphthoquinone (3) in Scheme 2. For this purpose, we monitored the pH of the reaction media for a representative entry (entry 3, Table 2) throughout the progress of the reaction and studied this reaction based on the formation of possible condensation adducts as intermediates. We successfully isolated and characterized (see Experimental Section) the chalcone derivative, 5-(4-methoxybenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (6-3), from the reaction of barbituric acid (1-3) and 4-methoxybenzaldehyde (2-3) in aqueous ethanol (1:1 v/v) at ambient conditions, as an intermediate with 86% yield, having the physical and spectral data in full agreement with those reported in the literature.70 In the next step, the isolated intermediate 6-3 produced the desired product, 5-(4methoxyphenyl)-1H-benzo[6,7]chromeno[2,3-d]pyrimidine2,4,6,11(3H,5H)-tetraone (4-3), upon reaction with 2-hydroxy1,4-naphthoquinone (3) under the same reaction conditions. In favor of our proposition, we also carried out a similar reaction between 4-methoxybenzaldehyde (2-3) and 2-hydroxy-1,4naphthoquinone (3) in aqueous ethanol (1:1 v/v) under identical reaction conditions and observed that the rate of this condensation reaction was too slow and the reaction was not completed within a reasonable time frame in comparison to the former case. The results of pH monitoring throughout the progress of this representative entry 3 are quite logical with the proposed paththe mixture of barbituric acid (1-3; 0.5 mmol) and 4methoxybenzaldehyde (2-3; 0.5 mmol) in aqueous ethanol (1:1 v/v; 4 mL) recorded a pH of 3.11, and under this acidic condition, a Claisen−Schmidt condensation takes place between the enolic tautomer (1′) of barbituric acid and the protonated aldehyde (2) to produce an aldol adduct 5 that eliminates one molecule of water, resulting in the formation of a chalcone intermediate 6 (6-3 was isolated and characterized). In the next step, 2-hydroxy-1,4-naphthoquinone (3) (0.5 mmol
heteroaryl aldehyde, furan-2-carbaldehyde (2-37), was also found to undergo the reaction with 2-thiobarbituric acid and 2hydroxy-1,4-naphthoquinone under the identical reaction conditions to produce 5-(furan-2-yl)-2-thioxo-2,3-dihydro-1Hbenzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione (437) in 96% yield (Table 2, entry 37). The overall results are summarized in Table 2. With this successful background, we were motivated to study the present protocol whether capable to furnish the bis(2-oxo-/ thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine4,6,11(5H)-trione) scaffold upon reaction with biscarboxaldehyde such as phthalaldehyde, isophthalaldehyde, and terephthalaldehyde. Accordingly, we performed the reaction between biscarboxaldehyde (1 equiv), barbituric acid (2 equiv), and 2hydroxy-1,4-naphthoquinone (2 equiv) in aqueous ethanol at ambient conditions and observed that both phthalaldehyde and isophthalaldehyde did not undergo any reaction (possibly because of the steric crowding), whereas terephthalaldehyde produced the desired bis-1H-benzo[6,7]chromeno[2,3-d]pyrimidine scaffold (4′) satisfactorily. To our delight, we were successful in synthesizing a set of three such new compounds, namely, 5,5′-(1,4-phenylene)bis(1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone) (4′-1), 5,5′-(1,4-phenylene)bis(1,3-dimethyl-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone) (4′-2), and 5,5′(1,4-phenylene)bis(2-thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione) (4′-3), in 98, 92, and 94% yield, respectively, within 18−22 h, using this methodology (Table 3). All products (4-1−4-37 and 4′-1−4′-3) were isolated pure just by washing with cold aqueous ethanol. All isolated products were new and were fully characterized based on their analytical data and detailed spectral studies including Fourier transform infrared (FT-IR), 1H NMR, 13C NMR, and distortionless enhancement by polarization transfer (DEPT)-135. We herein propose a possible mechanism for the aqueous ethanol-mediated one-pot synthesis of 5-aryl-2-oxo-/thioxo-2,35029
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Table 4. Green Metrics (EMY, AE, AEf, CE, RME, OE, and MP) for Three Representative Compounds (4-1, 4-15, and 4-32)a
a
entry
product
yield (%)
EMY (%)
AE (%)
AEf (%)
CE (%)
RME (%)
OE (%)
MP (%)
1 2 3
4-1 4-15 4-32
99 95 92
90.20 87.55 84.68
91.23 92.27 92.32
90.32 87.67 84.94
98.00 94.88 91.80
90.19 87.55 85.04
98.86 94.88 91.11
10.04 10.97 10.67
Higher is the value, greener is the process.
of which recorded a pH of 3.92 in 4 mL of aqueous ethanol) undergoes Michael addition with the chalcone intermediate 6 to produce the nucleophilic adduct 7, which subsequently takes part in a facile intramolecular ring closure via a 6-exo-trig process, generating the cycloadduct 8 that eventually furnishes the desired product 4 upon the elimination of water as a green waste (Scheme 2). It is worth noting that we successfully reused the reaction media containing the residual solvent and substrates obtained upon the filtration of the reaction mixture after the completion of the reaction up to the fourth run in the case of a representative entry (Table 2, entry 3), viz., reaction between barbituric acid, 4-methoxybenzaldehyde, and 2-hydroxy-1,4naphthoquinone. The desired product, 5-(4-methoxyphenyl)1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)tetraone (4-3), was isolated in almost identical yields (96− 98%) in all runs. We also examined the feasibility of the present method for a slightly scaled-up (on the gram scale; 10 mmol scale) experiment with the same entry (Table 2, entry 3) at room temperature in ethanol−water (20 mL; 1:1 v/v): the reaction was found to proceed smoothly, affording the desired product 4-3 in 96% isolated yield, and the product yield of this large-scale reaction is almost similar to that of the 0.5 mmol scale entry (Table 2, entry 3) in terms of yield and time. This experiment demonstrated the applicability of this catalyst-free room-temperature protocol for large-scale productions as well. We evaluated the green chemistry credentials of this newly developed one-pot synthesis protocol by performing a series of green metrics calculations71−82 such as effective mass yield (EMY), atom economy (AE), atom efficiency (AEf), carbon efficiency (CE), reaction mass efficiency (RME), optimum efficiency (OE), mass productivity (MP), mass intensity (MI) and process mass intensity (PMI), E-factor, solvent intensity (SI), and water intensity (WI) for all synthesized compounds 4 (4-1−4-37) and 4′ (4′-1−4′-3) (see the Supporting Information). The calculated AE and AEf for the method range from 89.43 to 93.01% and from 80.53 to 92.08%, respectively, and are less than 100% because of the formation of H2O as the byproduct. The calculated CE (79.60−99.00%) for this process is also quite good. As the RME includes all reactant mass, yield, and AE, it is the most useful metric to determine the greenness of a process. Calculations of EMY (83.83− 91.86%) and RME (80.58−92.22%) also indicate the excellent green credential of the present method. Similarly, the evaluations of MI (7.32−10.15 g/g) and PMI (31.64−41.14 g/g) parameters also corroborate this fact. The calculated Efactors ranging from 0.09 to 0.19 are found to be very much supportive for the greenness of the present method. The other green parameters have also been found to be in order. Working formulas for green metrics, their calculations, and respective data for all entries are documented in the Supporting Information; Tables 4 and 5 offer such data for three representative entries.
Table 5. Green Metrics (PMI, MI, E-Factor, SI, and WI) for Three Representative Compounds (4-1, 4-15, and 4-32)a entry
product
PMI (g/g)
MI (g/g)
E (g/g)
SI (g/g)
WI (g/g)
1 2 3
4-1 4-15 4-32
40.46 36.63 37.56
9.97 9.13 9.37
0.11 0.14 0.18
17.72 15.98 16.38
21.63 19.50 20.00
a
Lower is the value, better is the process.
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CONCLUSIONS A simple, catalyst-free, energy-efficient, and conveniently practical method for easy access to a huge range of biologically interesting diverse and functionalized 5-aryl-2-oxo-/thioxo-2,3dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine4,6,11(5H)-triones 4 (4-1−4-37) and substituted 5,5′-(1,4phenylene)bis(2-oxo-/thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione) derivatives 4′ (4′-1−4′-3) has been developed from the one-pot MCR between barbituric/2-thiobarbituric acids (1), aromatic aldehydes (2), and 2-hydroxy-1,4-naphthoquinone (3) in aqueous ethanol at room temperature. The salient features of this present protocol include mild reaction conditions at room temperature, avoidance of catalyst, operational simplicity and clean reaction profiles, and excellent yields with high atom economy. In addition, the use of commercially available inexpensive starting materials and the ease of product isolation/purification without the aid of tedious column chromatography are added advantages of this present method, thereby satisfying the triple bottom line philosophy of green and sustainable chemistry.83 In addition, the reusability of the reaction media and the quite successful operation in gram-scale synthesis offer added advantages to this protocol. The present method satisfies green credentials at the best. Considering the synthetic importance of such biologically relevant multiheterocentric organic scaffolds, the present catalyst-free green methodology with operational simplicity may thus also afford cost-effective and environmentally friendlier ways for large-scale syntheses of these useful molecules.
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EXPERIMENTAL SECTION General Considerations. Infrared spectra were recorded using a Shimadzu (FT-IR 8400S) FT-IR spectrophotometer using a KBr disk. 1H and 13C NMR spectra were collected at 400 and 100 MHz, respectively, on a Bruker DRX spectrometer using CDCl3 and DMSO-d6 as solvents. Elemental analyses were performed with an Elementar Vario EL III Carlo Erba 1108 microanalyzer instrument. Melting point was recorded on a Chemiline CL-725 melting point apparatus and was uncorrected. Thin-layer chromatography (TLC) was performed using silica gel 60 F254 (Merck) plates. General Procedure for the Synthesis of Functionalized 5-Aryl-2-oxo-/thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-triones 4. A magnetic stir bar, barbituric/2-thiobarbituric acid (1; 0.5 mmol), aromatic aldehyde (2; 0.5 mmol), 2-hydroxy-1,4-naphthoqui5030
DOI: 10.1021/acsomega.7b00791 ACS Omega 2017, 2, 5025−5035
ACS Omega
Article
(CONH), 1645 (CONH), 1596, 1513, 1274, 1045 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 11.01 (br s, 2H, 2 × −NH), 8.08 (d, 2H, J = 8.8 Hz, Ar-H), 7.97 (t, 2H, J = 8.4, 7.6 Hz, ArH), 7.85−7.76 (m, 2H, Ar-H), 7.67−7.52 (m, 2H, Ar-H), 5.06 (br s, 1H, −CH) ppm. 13C NMR (100 MHz, DMSO-d6): δ 184.84 (CO), 184.62 (CO), 184.52 (2 × CONH), 151.41 (2C), 135.43, 135.28, 133.87, 131.25, 130.75, 126.61 (2C), 126.27 (2C), 126.05, 123.40 (2C), 111.61, 103.30, 41.30 (−CH) ppm. Elemental analysis: calcd (%) for C21H11N3O7: C, 60.44; H, 2.66; N, 10.07; found: C, 60.40; H, 2.67; N, 10.04. 4-(2,4,6,11-Tetraoxo-2,3,4,5,6,11-hexahydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidin-5-yl)benzaldehyde (4-12). Creamy yellow solid; yield 99% (0.198 g, 0.5 mmol scale); mp 191−192 °C; IR (KBr) νmax: 3205 (NH), 3090, 2846, 1709 (CO), 1676 (CHO), 1648 (CONH), 1600, 1580, 1461, 1275, 1045 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 11.09 (br s, 1H, −NH), 10.99 (br s, 1H, −NH), 9.93 (s, 1H, −CHO), 8.12− 8.05 (m, 1H, Ar-H), 7.96 (q, 2H, J = 8.4, 7.2, 6.4 Hz, Ar-H), 7.85−7.80 (m, 2H, Ar-H), 7.77 (d, 2H, J = 8.0 Hz, Ar-H), 7.61 (br s, 1H, Ar-H), 5.03 (br s, 1H, −CH) ppm. 13C NMR (100 MHz, DMSO-d6): δ 193.72 (CHO), 184.53 (2 × CO), 184.01 (CONH), 181.70 (CONH), 163.77, 162.06, 150.82, 140.32, 136.32, 135.30, 133.77, 132.72, 132.48, 130.61 (2C), 129.63, 129.21, 126.62, 126.24, 121.10, 31.39 (−CH) ppm. Elemental analysis: calcd (%) for C22H12N2O6: C, 66.00; H, 3.02; N, 7.00; found: C, 65.98; H, 3.03; N, 6.99. 4-(2,4,6,11-Tetraoxo-2,3,4,5,6,11-hexahydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidin-5-yl)benzonitrile (4-17). Pale yellow solid; yield 98% (0.208 g, 0.5 mmol scale); mp 188−190 °C; IR (KBr) νmax: 3080, 2971, 2234 (CN), 1698 (CO), 1642 (CONCH3), 1598, 1526, 1508, 1491, 1271, 1037 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.09−8.06 (m, 2H, Ar-H), 7.78 (dt, 1H, J = 7.6, 1.2 Hz, Ar-H), 7.71 (dt, 1H, J = 7.6, 7.4, 1.2, 0.8 Hz, Ar-H), 7.59 (dt, 4H, J = 8.8, 8.4, 2.8, 2.0 Hz, Ar-H), 5.06−5.04 (m, 1H, −CH), 3.22 (s, 6H, 2 × NCH3) ppm. 13C NMR (100 MHz, CDCl3): δ 184.08 (CO), 180.84 (CO), 167.06 (2 × CONCH3), 153.37, 151.69, 143.77, 135.70, 133.65, 132.71, 132.56 (2C), 132.24, 129.91, 129.12, 127.64, 127.14, 126.64, 119.83 (CN), 118.79, 111.42, 43.45 (−CH), 29.02 (NCH3), 28.91 (NCH3) ppm. Elemental analysis: calcd (%) for C24H15N3O5: C, 67.76; H, 3.55; N, 9.88; found: C, 67.74; H, 3.54; N, 9.91. 5-(4-Bromophenyl)-1,3-dimethyl-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone (4-19). Yellow solid; yield 99% (0.237 g, 0.5 mmol scale); mp 178−181 °C; IR (KBr) νmax: 3078, 2967, 1697 (CO), 1666 (CONCH3), 1589, 1517, 1276, 1038 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.07 (dq, 2H, J = 7.6, 5.6, 0.8 Hz, Ar-H), 7.76 (dt, 1H, J = 7.6, 1.2 Hz, Ar-H), 7.68 (dt, 1H, J = 7.6, 7.4, 1.6, 1.2 Hz, Ar-H), 7.42−7.36 (m, 4H, Ar-H), 4.94−4.92 (m, 1H, −CH), 3.20 (s, 3H, −NCH3), 3.19 (s, 3H, −NCH3) ppm. 13C NMR (100 MHz, CDCl3): δ 184.00 (CO), 181.06 (CO), 167.49 (CONCH3), 167.30 (CONCH3), 153.24, 151.85, 136.73, 135.56 (2C), 133.49, 132.75, 131.62 (2C), 130.92 (2C), 129.17, 127.40, 126.52, 121.81, 120.40, 43.90 (CH), 28.94 (NCH3), 28.83 (NCH3) ppm. Elemental analysis: calcd (%) for C23H15BrN2O5: C, 57.64; H, 3.15; N, 5.84; found: C, 57.61; H, 3.14; N, 5.82. 5-(Benzo[d][1,3]dioxol-5-yl)-1,3-dimethyl-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone (4-23). Golden-yellow solid; yield 98% (0.218 g, 0.5 mmol scale); mp 178−179 °C; IR (KBr) νmax: 3097, 2992, 1705 (CO), 1673 (CONCH3), 1647, 1588, 1494, 1275, 1035 cm−1. 1H NMR
none (3; 0.5 mmol), and 4 mL of aqueous ethanol (1:1 v/v) were transferred to an oven-dried reaction tube in a sequential manner at ambient conditions, and the reaction mixture was then stirred vigorously for a stipulated time frame (12−22 h). The progress of the reaction was monitored by TLC. Upon the completion of the reaction, a solid mass precipitated out and was filtered off, followed by the purification of the crude product just by washing with cold aqueous ethanol. The structure of each purified compound was confirmed by analytical as well as spectral studies including FT-IR, 1H NMR, 13C NMR, and DEPT-135. The spectral and analytical data of some selected compounds are given below: 5-Phenyl-1H-benzo[6,7]chromeno[2,3-d]pyrimidine2,4,6,11(3H,5H)-tetraone (4-1). Pale yellow solid; yield 99% (0.184 g, 0.5 mmol scale); mp 198−200 °C; IR (KBr) νmax: 3215 (NH), 3103, 2849, 1711 (CO), 1670 (CONH), 1648 (CONH), 1593, 1494, 1273, 1043 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 11.01 (br s, 2H, 2 × −NH), 7.97 (d, 2H, J = 7.2 Hz, Ar-H), 7.86−7.76 (m, 2H, Ar-H), 7.42 (br s, 2H, Ar-H), 7.23 (t, 2H, J = 7.2, 6.8 Hz, Ar-H), 7.15 (t, 1H, J = 6.8, 6.4 Hz, Ar-H), 4.88 (br s, 1H, −CH) ppm. 13C NMR (100 MHz, DMSO-d6): δ 184.43 (CO), 181.45 (CO), 169.69 (2 × CO), 151.66, 135.49, 133.99, 132.50, 129.69, 128.35 (5C), 127.06 (4C), 126.65, 126.27, 43.61 (−CH) ppm. Elemental analysis: calcd (%) for C21H12N2O5: C, 67.74; H, 3.25; N, 7.52; found: C, 67.69; H, 3.24; N, 7.49. 5-(4-Methoxyphenyl)-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone (4-3). Yellow solid; yield 97% (0.195 g, 0.5 mmol scale); mp 140−141 °C; IR (KBr) νmax: 3299 (NH), 3085, 2980, 2840, 1709 (CO), 1648 (CONH), 1639 (CONH), 1588, 1512, 1270, 1040 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.09 (d, 2H, J = 7.6 Hz, Ar-H), 7.76−7.67 (m, 3H, Ar-H), 7.19 (d, 1H, J = 8.4 Hz, Ar-H), 6.82 (d, 2H, J = 8.8 Hz, Ar-H), 6.16 (br s, 1H, −CH), 4.77 (br s, 2H, 2 × −NH), 3.77 (s, 3H, Ar-OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ 184.90 (2 × CO), 181.34 (2 × CONH), 154.83, 133.35 (2C), 132.85, 129.92, 129.76, 129.39 (2C), 127.33 (2C), 126.45 (2C), 122.87, 119.70, 113.91 (2C), 55.34 (ArOCH3), 37.16 (−CH) ppm. Elemental analysis: calcd (%) for C22H14N2O6: C, 65.67; H, 3.51; N, 6.96; found: C, 65.61; H, 3.52; N, 6.94. 5-(4-(Trifluoromethyl)phenyl)-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone (4-4). Reddishyellow solid; yield 96% (0.211 g, 0.5 mmol scale); mp 188− 190 °C; IR (KBr) νmax: 3234 (NH), 3190, 2979, 2869, 1711 (CO), 1691 (CO), 1670 (CONH), 1605, 1595, 1565, 1465, 1282, 1068 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 9.95 (br s, 2H, 2 × −NH), 7.97 (d, 1H, J = 7.2 Hz, Ar-H), 7.90 (dd, 1H, J = 7.6, 1.2 Hz, Ar-H), 7.78 (dt, 1H, J = 7.6, 1.2 Hz, Ar-H), 7.73−7.69 (m, 1H, Ar-H), 7.65 (t, 1H, J = 8.0, 6.0 Hz, Ar-H), 7.50 (d, 2H, J = 8.0 Hz, Ar-H), 7.27 (d, 1H, J = 8.0 Hz, Ar-H), 6.37 (br s, 1H, −CH) ppm. 13C NMR (100 MHz, DMSO-d6): δ 183.84 (2 × CO), 172.59 (CONH), 165.81 (CONH), 151.55, 151.05, 148.96, 134.51 (2C), 132.91, 131.41, 130.76, 129.25, 128.04 (2C), 126.41, 126.28, 125.78, 125.13 (CF3), 125.10, 88.81, 49.04 (−CH) ppm. Elemental analysis: calcd (%) for C22H11N2O5F3: C, 60.01; H, 2.52; N, 6.36; found: C, 60.03; H, 2.51; N, 6.34. 5-(4-Nitrophenyl)-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone (4-8). Creamy yellow solid; yield 99% (0.206 g, 0.5 mmol scale); mp 176−178 °C; IR (KBr) νmax: 3213 (NH), 3097, 2871, 1710 (CO), 1672 5031
DOI: 10.1021/acsomega.7b00791 ACS Omega 2017, 2, 5025−5035
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1331 (CS), 1277, 1243 (CS), 1047 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 11.68 (br s, 2H, 2 × −NH), 7.99−7.94 (m, 2H, Ar-H), 7.86−7.74 (m, 2H, Ar-H), 6.40 (br s, 2H, Ar-H), 6.18−6.17 (m, 1H, −CH), 3.63 (s, 3H, Ar-OCH3), 3.62 (s, 6H, 2 × Ar-OCH3) ppm. 13C NMR (100 MHz, DMSO-d6): δ 184.66 (CS), 183.42 (CO), 182.50 (CO), 173.42 (CO), 163.40, 160.45, 152.81, 137.27, 136.16, 134.51, 133.21, 132.80, 131.05, 126.39, 125.81, 124.79, 122.54, 111.44, 105.04, 94.38, 60.34 (Ar-OCH3), 56.47 (Ar-OCH3), 56.28 (Ar-OCH3), 33.01 (−CH) ppm. Elemental analysis: calcd (%) for C24H18N2O7S: C, 60.25; H, 3.79; N, 5.85; found: C, 60.21; H, 3.81; N, 5.83. 4-(4,6,11-Trioxo-2-thioxo-2,3,4,5,6,11-hexahydro-1Hbenzo[6,7]chromeno[2,3-d]pyrimidin-5-yl)benzaldehyde (436). Deep yellow solid; yield 93% (0.194 g, 0.5 mmol scale); mp 192−194 °C; IR (KBr) νmax: 3200 (NH), 3059, 2903, 1679 (CO & CHO), 1636 (CONH), 1603, 1548, 1429, 1364 (C S), 1276, 1043 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 11.76−11.68 (m, 1H, −NH), 11.51 (s, 1H, −NH), 9.92 (s, 1H, −CHO), 7.97 (q, 2H, J = 8.0, 7.6, 6.8 Hz, Ar-H), 7.84−7.77 (m, 2H, Ar-H), 7.74 (d, 2H, J = 8.4 Hz, Ar-H), 7.33 (d, 1H, J = 7.6 Hz, Ar-H), 6.93 (br s, 1H, Ar-H), 6.36 (br s, 1H, −CH) ppm. 13 C NMR (100 MHz, DMSO-d6): δ 193.67 (CS), 193.16 (CHO), 184.38 (CO), 182.87 (CO), 173.83 (CONH), 173.59, 163.84, 161.02, 134.75, 134.52, 133.37, 132.92, 130.59, 130.01, 129.88 (2C), 129.12, 128.12, 126.55, 126.00, 124.29, 33.50 (−CH) ppm. Elemental analysis: calcd (%) for C22H12N2O6: C, 63.46; H, 2.90; N, 6.73; found: C, 63.42; H, 2.89; N, 6.72. 5-(Furan-2-yl)-2-thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione (4-37). Dark yellow solid; yield 96% (0.181 g, 0.5 mmol scale); mp 162− 166 °C; IR (KBr) νmax: 3139 (NH), 3071, 1701 (CO), 1645 (CONH), 1555, 1523, 1352 (CS), 1285, 1031 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, 4H, J = 7.6 Hz, Ar-H), 7.79 (dt, 2H, J = 7.6, 0.8 Hz, Ar-H), 7.72 (dt, 1H, J = 7.6, 7.0, 1.2 Hz, Ar-H), 7.45 (br s, 2H, 2 × −NH), 6.36 (s, 1H, −CH) ppm. 13C NMR (100 MHz, DMSO-d6): δ 185.14 (CS), 182.09 (2 × CO), 167.49 (CO), 156.51, 152.87, 135.43, 133.29, 133.04, 129.57, 126.85 (2C), 126.65, 120.50, 117.16, 110.87 (2C), 107.34, 48.03 (−CH) ppm. Elemental analysis: calcd (%) for C19H10N2O5S: C, 60.31; H, 2.66; N, 7.40; found: C, 60.26; H, 2.65; N, 7.38. 5,5′-(1,4-Phenylene)bis(1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone) (4′-1). Brownish-yellow solid; yield 98% (0.326 g, 0.5 mmol scale); mp 199−200 °C; IR (KBr) νmax: 3208 (NH), 3095, 2851, 1708 (CO), 1646 (CONH), 1589, 1506, 1275, 1043 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 11.67 (br s, 1H, −NH), 10.99−10.96 (m, 2H, 2 × −NH), 10.48 (br s, 1H, −NH), 8.10−8.06 (m, 1H, Ar-H), 7.97−7.91 (m, 4H, Ar-H), 7.78 (d, 2H, J = 6.8 Hz, Ar-H), 7.74 (d, 2H, J = 7.2 Hz, Ar-H), 7.31 (br s, 2H, Ar-H), 6.98 (br s, 1H, Ar-H), 4.81−4.78 (m, 1H, −CH), 4.51−4.49 (m, 1H, −CH) ppm. 13C NMR (100 MHz, DMSO-d6): δ 184.06 (2 × CO), 181.25 (2 × CO), 169.45 (2 × CONH), 163.59 (2 × CONH), 161.88, 155.98 (2C), 153.43, 151.47 (2C), 150.62 (2C), 136.16, 135.20 (2C), 133.74 (2C), 132.31 (2C), 130.00 (2C), 129.01 (2C), 126.44 (2C), 126.05 (2C), 121.86, 92.28 (2C), 51.19 (−CH), 43.40 (−CH) ppm. Elemental analysis: calcd (%) for C36H18N4O10: C, 64.87; H, 2.72; N, 8.41; found: C, 64.81; H, 2.71; N, 8.39. 5,5′-(1,4-Phenylene)bis(1,3-dimethyl-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-2,4,6,11(3H,5H)-tetraone) (4′-2). Light yellow solid; yield 92% (0.333 g, 0.5 mmol scale); mp 193−196 °C; IR (KBr) νmax: 3033, 2961, 2892, 1677 (CO),
(400 MHz, DMSO-d6): δ 7.99−7.95 (m, 2H, Ar-H), 7.85−7.77 (m, 2H, Ar-H), 7.08 (d, 1H, J = 8.0 Hz, Ar-H), 6.79−6.78 (m, 1H, Ar-H), 6.74 (d, 1H, J = 8.0 Hz, Ar-H), 5.93 (s, 2H, OCH2O), 4.85 (br s, 1H, −CH), 3.01 (s, 6H, 2 × −NCH3) ppm. 13C NMR (100 MHz, DMSO-d6): δ 184.27 (2 × CO), 168.05 (CONCH3), 165.37 (CONCH3), 156.11, 152.24 (3C), 147.12 (2C), 135.29, 133.77 (2C), 126.48 (2C), 126.12, 107.97 (3C), 102.77, 101.18 (−OCH2O−), 43.62 (−CH), 29.07 (NCH3), 28.44 (NCH3) ppm. Elemental analysis: calcd (%) for C24H16N2O7: C, 64.87; H, 3.63; N, 6.30; found: C, 64.84; H, 3.61; N, 6.28. 3-(1,3-Dimethyl-2,4,6,11-tetraoxo-2,3,4,5,6,11-hexahydro1H-benzo[6,7]chromeno[2,3-d]pyrimidin-5-yl)benzaldehyde (4-24). Dark yellow solid; yield 99% (0.212 g, 0.5 mmol scale); mp 180−182 °C; IR (KBr) νmax: 3077, 2986, 1700 (CO), 1667 (CHO), 1587, 1521, 1459, 1274, 1041 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H, −CHO), 8.00−7.95 (m, 2H, Ar-H), 7.86−7.77 (m, 4H, Ar-H), 7.72 (d, 1H, J = 7.2 Hz, ArH), 7.48 (t, 1H, J = 7.6, 7.2 Hz, Ar-H), 5.13 (br s, 1H, −CH), 3.04 (s, 6H, −NCH3) ppm. 13C NMR (100 MHz, DMSO-d6): δ 193.71 (2 × CO), 184.36 (−CHO), 181.13 (CONCH3), 167.90 (CONCH3), 152.24, 136.35, 135.63, 135.25, 135.15, 133.82, 132.39, 130.34, 130.24, 130.12, 129.01 (2C), 128.34, 126.52 (2C), 126.17, 42.51 (−CH), 28.50 (2 × NCH3) ppm. Elemental analysis: calcd (%) for C24H16N2O6: C, 67.29; H, 3.76; N, 6.54; found: C, 67.25; H, 3.77; N, 6.52. 5-(4-Methoxyphenyl)-2-thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione (4-27). Bright yellow solid; yield 97% (0.203 g, 0.5 mmol scale); mp 174−176 °C; IR (KBr) νmax: 3149 (NH), 3075, 2934, 1696 (CO), 1656 (CONH), 1596, 1527, 1508, 1435, 1343 (CS), 1270, 1214 (CS), 1004 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 11.69 (br s, 2H, NH), 7.98−7.89 (m, 2H, Ar-H), 7.81−7.74 (m, 2H, Ar-H), 7.07 (d, 1H, J = 9.2 Hz, Ar-H), 6.99 (d, 1H, J = 7.6 Hz, Ar-H), 6.74 (dd, 2H, J = 7.8, 2.0 Hz, Ar-H), 6.16−6.15 (m, 1H, −CH), 3.67 (s, 3H, Ar-OCH3) ppm. 13C NMR (100 MHz, DMSO-d6): δ 184.96 (CS), 181.90 (CO), 178.88 (CO), 164.59 (CONH), 163.56, 162.83, 160.57, 156.59, 156.33, 138.56, 129.87, 128.34, 126.56, 126.18, 125.89, 116.21, 114.72, 113.86, 113.61, 94.79, 55.52 (Ar-OCH3), 32.17 (−CH) ppm. Elemental analysis: calcd (%) for C22H14N2O5S: C, 63.15; H, 3.37; N, 6.70; found: C, 63.10; H, 3.36; N, 6.69. 4-(4,6,11-Trioxo-2-thioxo-2,3,4,5,6,11-hexahydro-1Hbenzo[6,7]chromeno[2,3-d]pyrimidin-5-yl)benzonitrile (429). Reddish-yellow solid; yield 97% (0.200 g, 0.5 mmol scale); mp 172−174 °C; IR (KBr) νmax: 3237 (NH), 3041, 2231 (CN), 1671 (CO), 1666 (CONH), 1600, 1590, 1579, 1533, 1362 (CS), 1277, 1226 (CS), 1016 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 11.56 (br s, 2H, 2 × −NH), 7.96 (q, 2H, J = 7.6, 7.2, 4.8 Hz, Ar-H), 7.83−7.74 (m, 2H, Ar-H), 7.65 (d, 2H, J = 8.4 Hz, Ar-H), 7.30 (d, 2H, J = 7.6 Hz, Ar-H), 6.32 (br s, 1H, −CH) ppm. 13C NMR (100 MHz, DMSO-d6): δ 186.94 (CS), 184.08 (CO), 182.68 (CO), 173.72 (CONH), 163.76, 160.98, 148.75, 134.52, 133.18, 132.80, 132.22 (2C), 131.16, 129.28, 128.37, 126.39, 125.84, 123.83, 119.69 (CN), 108.28, 93.60, 33.20 (−CH) ppm. Elemental analysis: calcd (%) for C22H11N3O4S: C, 63.92; H, 2.68; N, 10.16; found: C, 63.87; H, 2.66; N, 10.14. 2-Thioxo-5-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1Hbenzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione (434). Golden-yellow solid; yield 93% (0.222 g, 0.5 mmol scale); mp 198−200 °C; IR (KBr) νmax: 3190 (NH), 3050, 2943, 1703 (CO), 1675 (CONH), 1648, 1592, 1513, 1432, 5032
DOI: 10.1021/acsomega.7b00791 ACS Omega 2017, 2, 5025−5035
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1671 (CO), 1663 (CONCH3), 1645 (CONCH3), 1623, 1585, 1459, 1277, 1042 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 8.03−7.99 (m, 1H, Ar-H), 7.97−7.94 (m, 4H, Ar-H), 7.82− 7.75 (m, 5H, Ar-H), 7.27 (br s, 2H, Ar-H), 4.90 (br s, 1H, −CH), 4.68 (br s, 1H, −CH), 3.19−3.16 (m, 3H, −NCH3), 3.06 (br s, 3H, −NCH3), 2.98 (br s, 6H, 2 × −NCH3) ppm. 13 C NMR (100 MHz, DMSO-d6): δ 184.74 (CO), 184.29 (CO), 179.74 (CO), 173.29 (CO), 171.36 (2 × CONCH3), 168.48 (2 × CONCH3), 152.43 (2C), 152.40 (2C), 139.23, 135.09 (2C), 133.96 (2C), 133.87, 129.68 (2C), 128.96 (2C), 126.66 (2C), 126.64 (2C), 126.59 (2C), 126.56 (2C), 126.00 (2C), 84.80 (2C), 42.46 (2 × −CH), 29.21 (2 × NCH3), 28.59 (2 × NCH3) ppm. Elemental analysis: calcd (%) for C40H26N4O10: C, 66.48; H, 3.63; N, 7.75; found: C, 66.51; H, 3.62; N, 7.78. 5,5′-(1,4-Phenylene)bis(2-thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione) (4′-3). Pale yellow solid; yield 94% (0.329 g, 0.5 mmol scale); mp 199−200 °C; IR (KBr) νmax: 3159 (NH), 3041, 2897, 1719 (CO), 1646 (CONH), 1590, 1544, 1444, 1336 (CS), 1276, 1045 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 11.94 (br s, 4H, 4 × −NH), 7.99−7.92 (m, 4H, Ar-H), 7.81−7.73 (m, 4H, ArH), 7.34−7.26 (m, 1H, Ar-H), 6.95 (br s, 3H, Ar-H), 6.16− 6.13 (m, 2H, 2 × −CH) ppm. 13C NMR (100 MHz, DMSOd6): δ 194.65 (CS), 193.01 (CS), 185.16 (2 × CO), 182.06 (2 × CO), 173.42 (2 × CONH), 163.11 (2C), 159.84 (2C), 137.45 (2C), 134.64 (2C), 133.47 (2C), 132.59 (2C), 130.89 (2C), 126.84 (2C), 126.47 (4C), 125.93 (2C), 124.42 (2C), 94.75 (2C), 42.89 (−CH), 32.62 (−CH) ppm. Elemental analysis: calcd (%) for C36H18N4O8S2: C, 61.89; H, 2.60; N, 8.02; found: C, 61.86; H, 2.59; N, 8.00. Isolation and Characterization of a Representative Chalcone Intermediate (Benzylidene Barbituric Acid) 63. An oven-dried sealed tube was charged with a magnetic stir bar, barbituric acid (1-3; 0.5 mmol), 4-methoxybenzaldehyde (2-3; 0.5 mmol), and 4 mL of aqueous ethanol (1:1 v/v) in a sequential manner at ambient conditions, and the reaction mixture was then stirred for 5 h. The progress of the reaction was monitored by TLC. Upon the completion of the reaction, a yellow solid mass precipitated out, was filtered off, and was washed with cold aqueous ethanol to obtain pure 5-(4methoxybenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (6-3) having the physical and spectral data in full agreement with those reported in the literature.70 5-(4-Methoxybenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (6-3). Bright yellow solid; yield 86% (0.106 g, 0.5 mmol scale); mp 271−274 °C; IR (KBr) νmax: 3207 (NH), 3079, 2986, 1682 (−CHCCO−), 1672 (−CONH), 1658, 1548, 1509, 1461, 1272, 1047 cm−1. 1H NMR (400 MHz, DMSOd6): δ 11.31 (br s, 1H, −NH), 11.18 (br s, 1H, −NH), 8.37 (d, 2H, J = 8.8 Hz, Ar-H), 8.25 (s, 1H, −CHC−), 7.07 (d, 2H, J = 8.8 Hz, Ar-H), 3.88 (s, 3H, Ar-OCH3) ppm. 13C NMR (100 MHz, DMSO-d6): δ 164.38 (CONH), 163.90 (CONH), 162.64, 155.40 (−CHC−), 150.67 (−NHCONH−), 137.94 (2C), 125.62, 116.01 (−CHC−), 114.41 (2C), 56.15 (Ar-OCH3) ppm. Elemental analysis: calcd (%) for C12H10N2O4: C, 58.54; H, 4.09; N, 11.38; found: C, 58.51; H, 4.08; N, 11.36.
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Spectral and analytical data for all synthesized compounds (4-1−4-37 and 4′-1−4′-3) and the chalcone intermediate 6-3 including the scanned copies of the respective 1H NMR and 13C NMR spectra and working formulas for the calculations of green metrics and respective calculated data for all synthesized compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected], goutam.brahmachari@ visva-bharati.ac.in. ORCID
Goutam Brahmachari: 0000-0001-9925-6281 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are thankful to the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India, New Delhi, for generous financial support (grant no. EMR/2014/001220). They are also thankful to CDRI, Lucknow, and Department of Chemistry, Visva-Bharati University, for spectral measurements.
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DEDICATION This paper is dedicated to Professor Basudeb Basu on the occasion of his 61st birthday. REFERENCES
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