Development of a Water-Mediated and Catalyst-Free Green Protocol

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Development of a water-mediated and catalyst-free green protocol for easy access of a huge array of diverse and densely functionalized pyrido[2,3-d:6,5-d']dipyrimidines via one-pot multicomponent reaction under ambient conditions Goutam Brahmachari, Khondekar Nurjamal, Indrajit Karmakar, Sanchari Begam, Nayana Nayek, and Bhagirath Mandal ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b02696 • Publication Date (Web): 03 Sep 2017 Downloaded from http://pubs.acs.org on September 3, 2017

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ACS Sustainable Chemistry & Engineering

Development of a water-mediated and catalyst-free green protocol for easy access of a huge array of diverse and densely functionalized pyrido[2,3-d:6,5d']dipyrimidines via one-pot multicomponent reaction under ambient conditions Goutam Brahmachari*, Khondekar Nurjamal, Indrajit Karmakar, Sanchari Begam, Nayana Nayek and Bhagirath Mandal Laboratory of Natural Products & Organic Synthesis, Department of Chemistry, Visva-Bharati (a Central University), Santiniketan-731 235, West Bengal, India E-mail: [email protected]; [email protected] Tel. 91-3463-264017 *Corresponding author: Prof. Dr. Goutam Brahmachari (http://orcid.org/0000-0001-9925-6281)

__________________________________________________________________ Abstract A water-mediated and catalyst-free simple protocol for easy access of a huge array of pharmaceuticallyinteresting and diversely functionalized 5-alkyl/aryl/heteroaryl-10-alkyl/aryl-2,8-dioxo/dithioxo-9,10dihydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,3H,5H,7H)-dione derivatives 4 (4-1‒4-42) and 5,5'-(1,4phenylene)bis(10-alkyl/aryl-2,8-dioxo/dithioxo-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,3H, 5H,7H)-dione) 4′ (4′-1‒4′-8) has been developed based on a one-pot multicomponent reaction between barbituric/N,N-dimethylbarbituric/2-thiobarbituric acids (1), substituted amines (2) and aldehydes (3) under ambient conditions. The salient features of this protocol are the clean reaction profile, use of no added catalyst, water as reaction media, mild reaction conditions at room temperature, energy-efficiency, easy isolation of products, no need of column chromatographic purification, high atom-economy and low E-factor, good to excellent yields, and reusability of reaction media.

__________________________________________________________________ Keywords: Water-mediated reaction, catalyst-free, one pot multi-component reaction, green synthesis, functionalized pyrido[2,3-d:6,5-d']dipyrimidines

INTRODUCTION Heterocyclic moieties, particularly polyfunctionalized heterocycles (PFHs), are widely prevalent in bioactive natural products as well as in the marketed pharmaceuticals, agrochemicals, dyes 1

ACS Paragon Plus Environment


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and many other application-oriented materials.1−7 Hence, research on the synthesis of PFHs has gained special attention. Among N-heterocycles, pyrimidine and its derivatives are reported for a wide range of biological profiles including antioxidant, anti-inflammatory, immunomodulating, antibacterial, antiviral and antitumor activity.8−12 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 as CNS depressants.13−21 Combination of barbituric/thiobarbituric acid moiety with other pharmacophoric groups, thus, may offer a possibility to synthesize numerous derivatives with desired potential biological effects. With this view, pyrimidine-fused pyridines, especially pyrido[2,3-d]pyrimidines, have been studied intensively over the recent past due to their wide spectrum of promising biological activities.22−29

Among various

tricyclic

pyrimidopyridopyrimidines, pyrido[2,3-d:6,5-

d']dipyrimidine scaffold has attracted much attention because a handful of such derivatives possess considerable α-glucosidase and α-amylase inhibitory activity,30 antibacterial,31,32 antiviral,33 NAD-type redox catalytic,34 and anticorrosive35,36 properties. In addition, such scaffold has been reported to have the potential in self-assembling to constitute supramolecular structure as well.37 Literature survey revealed that there are a number of methods for the synthesis of N10unsubstituted

9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones

using a variety of catalysts such as DBU,38 SBA-15-SO3H,39 [H-NMP]+[HSO4]−,32 γFe2O3@HAp-SO3H,40 nano-CuFe2O4,41−43 nano-Fe3O4,44 and these protocols required the use of organic solvents, heating and/or refluxing, microwave irradiation, and ultrasound irradiation. However, syntheses of N10-substituted dihydropyrido[2,3-d:6,5-d']dipyrimidines were reported only by the research group of Khalafi-Nezhad from the three-component condensation reaction of barbituric acids, anilines and aromatic aldehydes or sugars upon refluxing the reactants in ethanol either in the presence of phosphotungstic acid (TPA)45 or p-toluenesulfonic acid46 or magnetic nanoparticles-supported tungstic acid (MNP-TA)47 as the catalyst. Under this purview and in continuation to our endeavors in developing alternative green protocols for biologically relevant compounds,48−60 we herein wish to report a water-mediated, convenient, and catalystfree practical method for the synthesis of a huge array of functionalized 5-alkyl/aryl/heteroaryl2


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10-alkyl/aryl-2,8-dioxo/dithioxo-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine4,6(1H,3H,5H,7H)-dione derivatives (4/4′) from the one-pot multicomponent reaction between barbituric/N,N-dimethylbarbituric/2-thiobarbituric acids (1), diverse amines (2) and aldehydes (3) in water at ambient conditions (25-30 οC); the overall results are summarized in Scheme 1. The key advantages of this newly developed protocol are the clean reaction profile, use of no added catalyst, water as reaction media, mild reaction conditions at room temperature, energyefficiency, use of commercially available low-cost starting materials, no need of column chromatographic purification, high atom-economy and low E-factor, and good to excellent yields. From green chemistry perspectives, make use of water as safe and green solvent,61−66 implementation of one-pot multicomponent reaction (MCR) strategy with huge operational benefits,67−72 and enabling useful organic syntheses involving molecular hybridization (MH)73−75 exploiting just ambient reaction conditions76−83 are the steps forward to the cause of green and sustainable chemistry. O R1

N +

X

N

R2

NH2

O

R1 Substituted barbituric acids (1; 1.0 mmol)

+

Catalyst-free H2O (4 mL)

R3 CHO

Substituted aldehydes (3; 0.5 mmol)

7

6

N

(No Column Chromatography)

X

9

O 4

3

N

5

8

Room temperature (25-30 C) stirring for 10-18 h Substituted amines (2; 0.5 mmol)

R3

O R1

N R1

R1

10

1

N R2

N 2 X R1

Functionalized 9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidines (4/4') 50 entries (yield: 57-93%)

R1 = H, CH3 R2 = C6H5, 4-CH3C6H4, 2-OCH3C6H4, 3-OCH3C6H4, 4-OCH3C6H4, 4-BrC6H4, 4-CF3C6H4, 4-OCF3C6H4, 4-S(CH3)C6H4, 4-S(CF3)C6H4, 3,5-di-CF3C6H3, CH3CH2CH2, CH3CH2CH2CH2, CH3(CH2)4CH2, cyclohexyl, L-tyrosinyl, L-alanyl, D-glucosaminyl R3 = 2-NO2C6H4, 3-NO2C6H4, 4-NO2C6H4, 4-CNC6H4, 4-CF3C6H4, 4-OCH3C6H4, 2-BrC6H4, 3-BrC6H4, 4-BrC6H4, 2-ClC6H4, 2-FC6H4, 4-FC6H4, 3,4-di-OCH3C6H3, 3,4,5-tri-OCH3C6H2, 4-CHOC6H4, 9-anthracenyl, CH3CH2CH2, 2-furyl, 3,4-OCH2OC6H3, (CH3)2CH, 2-naphthyl X = O, S

Scheme 1. Catalyst-free one-pot room temperature synthesis of diversely functionalized 5alkyl/aryl/heteroaryl-10-alkyl/aryl-2,8-dioxo/dithioxo-9,10-dihydropyrido[2,3-d:6,5d']dipyrimidine-4,6(1H,3H,5H,7H)-diones (4/4′) RESULTS AND DISCUSSION Based on critical survey of the literature on catalyst-free organic transformations coupled with our own experiences in performing this kind of organic syntheses,84,85 we envisioned that such 3



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9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraone scaffold might be constructed out of a one-pot multicomponent reaction of its starting constituents such as barbituric acid, amine and aldehyde without the aid of any catalyst in the presence of a suitable solvent. First we checked our model reaction with a mixture of barbituric acid (1-1; 2.0 equiv.), aniline (2-1; 1.0 equiv.) and 4-nitrobenzaldehyde (3-1; 1.0 equiv.) in the absence of any catalyst in aqueous medium (4 mL) under ambient conditions. To our delight the reactants resulted the desired compound, 5-(4-nitrophenyl)-10-phenyl-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine2,4,6,8(1H,3H,5H,7H)-tetraone (4-1), in 85% yield on stirring for 12h (Table 1, entry 1). To check the impact of water as solvent, we then carried out the same reaction under neat condition, and observed that the reaction practically did not occur at all (Table 1, entry 2). This fact demonstrated the effectiveness of water as a suitable medium for this reaction. Compound 4-1 was characterized by its analytical and spectral properties. The results are summarized in Table 1. Table 1 Optimization of reaction conditions for the synthesis of substituted 9,10-dihydropyrido[2,3d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones (4) NO2

O HN

+ N H

O

CHO

NH2 +

O

1-1

Entry

NO2 2-1

Catalyst-free experimental conditions room temperature (RT) time (h)

O

O

HN O

NH N H

N

3-1

N H

O

4-1

1

Solvent H2O

Time (h) 12

2

Neat

24

Yield(%)a,b 85 Trace

a

Reaction Conditions: barbituric acid (1.0 mmol), aniline (0.5 mmol), and 4-nitrobenzaldehyde (0.5 mmol) in 4 mL of water/neat at room temperature (25-30 οC) without any added catalyst. bIsolated yields.

Under the optimized conditions, we then carried out the reaction between barbituric acid, 4methylaniline and 4-nitrobenzaldehyde, and another between barbituric acid, 4-methylaniline and 3-nitrobenzaldehyde; both the reactions furnished the respective desired products, viz. 5-(44


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nitrophenyl)-10-(p-tolyl)-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)tetraone (4-2) (Table 2, entry 2) and 5-(3-nitrophenyl)-10-(p-tolyl)-9,10-dihydropyrido[2,3d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraone (4-3) (Table 2, entry 3), in 91% and 88% yield, respectively, within 11-12 h. To check the generality as well as the effectiveness of this newly developed protocol, barbituric acid was reacted with diverse aromatic amines (bearing substituents like bromo, trifluoromethyl, methoxyl, and trifluoromethoxyl at varying positions) and aromatic aldehydes containing the functionalities such as bromo, chloro, cyano, trifluoromethyl, mono-, di- and tri-methoxyls, and nitro using identical reaction conditions. All of these varying twelve entries underwent the reaction smoothly affording the corresponding 5,10-diaryl-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones

(4-

4‒4-15) (Table 2, entries 4-15) in good to excellent yields ranging from 57 to 93% at room temperature within 10-16 h. The variation in the yields of these products (4-1‒4-15) indicates that the presence of an electron-withdrawing function in the reacting aldehyde and an electronreleasing function in amine substrate facilitates the reaction as expected. Formation of 10-(4(trifluoromethyl)phenyl)-5-(3,4,5-trimethoxyphenyl)-9,10-dihydropyrido[2,3-d:6,5d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraone (4-14; Table 2, entry 14) in somewhat moderate yield of 57% at 16 h could be rationalized from the fact that the 4-CF3 substituent offers a strong electron-withdrawing effect on the amine, while 3,4,5-trimethoxyl moiety also imposes some steric constraint towards the reactivity of the aldehyde. Similar situation also prevails for entry 15 where 4-OCF3 group reduces the reactivity of the amine (2-15) by imposing a strong electronwithdrawing effect, and the reactivity of the aldehyde (3-15) is retarded by steric crowding offered by its 3,4-dimethoxyl substituents, giving a yield of 60% for 5-(3,5-dimethoxyphenyl)10-(4-(trifluoromethoxy)phenyl)-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine2,4,6,8(1H,3H,5H,7H)-tetraone (4-15). Under the same reaction conditions, aliphatic amines such as n-propyl amine (2-16) and nhexylamine (2-17) also reacted smoothly with barbituric acid and 2-/3-nitrobenzaldehydes affording the respective desired products, 5-(2-nitrophenyl)-10-propyl-9,10-dihydropyrido[2,3d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraone (4-16; Table 2, entry 16) and 10-hexyl-5(3-nitrophenyl)-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraone (4-17; Table 2, entry 17) with moderate yields of 63-66% at 12h. Then we thought about amino 5



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acid as an interesting variant of aliphatic/aromatic amines, and we were delighted to synthesize 3-(4-hydroxyphenyl)-2-(5-(4-nitrophenyl)-2,4,6,8-tetraoxo-1,2,3,4,6,7,8,9-octahydropyrido[2,3d:6,5-d']dipyrimidin-10(5H)-yl)propanoic acid (4-18; Table 2, entry 18) from the reaction of tyrosine (2-18) with the mixture of barbituric acid and 4-nitrobenzaldehyde in water at ambient conditions in 70% yield at 16h. In another two occasions, when terephthalaldehyde (4formylbenzaldehyde) was reacted with barbituric acid and substituted amines under these reaction conditions, we isolated the corresponding products 4-19 (82% at 12h; Table-2, entry 19) and 4-20 (77% at 14h; Table-2, entry 20) with the 4-formyl group intact in their molecular structures. Such novel series of compounds with free formyl group are of much chemical interest. Inspired by these results, we then replaced unsubstituted barbituric acid with N,Ndimethylbarbituric acid, and carried out a set of seven different reactions upon treating this substituted barbituric acid (2 equiv.) with diverse amines (viz. 4-(methylthio)aniline, alanine, tyrosine,

glucosamine, 4-trifluoromethylaniline) (1 equiv.) and aldehydes (viz. 3,4-

dimethoxybenzaldehyde, 9-anthracenylaldehyde, 2-/4-fluorobenzaldehyde, terephthalaldehyde) (1 equiv.) in water under the catalyst-free conditions just at room temperature. To our delight, all the seven reactions produced the expected products of a new series of substituted 9,10dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8-tetraones (4-21 – 4-27) (Table 2, entries 21-27) with yields ranging from 62-80% within 14-18 h. Encouraged by these results, we then planned to replace barbituric acid/N,Ndimethylbarbituric acid with 2-thiobarbituric acid so as to further extend the applicability of this newly developed protocol in generating 2-thioxo-substituted analogues. For this purpose, we performed a set of three varying reactions (Table 2, entries 28-30) by treating 2-thiobarbituric acid (2 equiv.) with three separate reactant-mixtures of aniline (2-28; 1 equiv.) and 4methoxybenzaldehyde (3-28; 1 equiv.), furaldehyde (3-29; 1 equiv.), and

4-trifluoromethylaniline (2-29; 1 equiv.) and 2-

4-trifluoromethoxyaniline (2-30; 1 equiv.) and 4-

bromobenzaldehyde (3-30; 1 equiv.) in water under the same reaction conditions, and we were delighted to obtain the respective desired products, 5-(4-methoxyphenyl)-10-phenyl-2,8dithioxo-2,3,7,8,9,10-hexahydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,5H)-dione (4-28), 5(furan-2-yl)-2,8-dithioxo-10-(4-(trifluoromethyl)phenyl)-2,3,7,8,9,10-hexahydropyrido[2,36


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d:6,5-d']dipyrimidine-4,6(1H,5H)-dione

(4-29),

and

5-(4-bromophenyl)-2,8-dithioxo-10-(4-

(trifluoromethoxy)phenyl)-2,3,7,8,9,10-hexahydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,5H)dione (4-30) with 83%, 75% and 78% yields, respectively, within 14-16 h. We, furthermore, utilized the optimized reaction conditions to synthesize a series of twelve more new 5-aryl-2,8dithioxo-10-alkyl/aryl-2,3,7,8,9,10-hexahydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,5H)dione derivatives (4-31‒4-42) (Table 2, entries 31-42) from the one-pot reaction of 2thiobarbituric acid (2 equiv.) with a varying range of aliphatic/aromatic amines (2; 1 equiv.) and aldehydes (3; 1 equiv.) in aqueous medium without the aid of any catalyst under ambient conditions. All the reactions were successfully completed furnishing the expected products 4-314-42 (Table 2, entries 31-42) with good yields ranging from 67-81% within 14-18h. The overall results are summarized in Table 2.

7



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Table 2 Synthesis of diversely substituted 5-alkyl/aryl/heteroaryl-10-alkyl/aryl-2,8-dioxo/dithioxo-9,10-dihydropyrido[2,3-d:6,5d']dipyrimidine-4,6(1H,3H,5H,7H)-diones (4)

Time (h)

Yield (%)a,b E-Factor (g/g)

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

12 11 12 10 12 12 14 14 14 12 13 12 14

85 91 88 92 93 87 74 62 82 86 65 87 78

4-14 4-15 4-16

16 14 12

57 60 63

Entry Substituent (X)

Substituent (R1)

Substituent (R2)

Substituent (R3)

Product

1 2 3 4 5 6 7 8 9 10 11 12 13

O O O O O O O O O O O O O

H H H H H H H H H H H H H

C6H5 4-CH3C6H4 4-CH3C6H4 4-OCH3C6H4 4-BrC6H4 4-OCH3C6H4 4-CH3C6H4 4-OCH3C6H4 2-OCH3C6H4 3-OCH3C6H4 4-OCH3C6H4 4-BrC6H4 4-CF3C6H4

4-NO2C6H4 4-NO2C6H4 3-NO2C6H4 4-NO2C6H4 4-CNC6H4 4-CF3C6H4 4-OCH3C6H4 4-OCH3C6H4 4-BrC6H4 3-BrC6H4 2-BrC6H4 2-ClC6H4 4-CF3C6H4

14 15 16

O O O

H H H

4-CF3C6H4 4-OCF3C6H4 CH3CH2CH2

3,4,5-tri-OCH3C6H2 3,4-di-OCH3C6H3 2-NO2C6H4

8


Melting point ( οC) Found

Reported

0.32 0.23 0.28 0.21 0.19 0.28 0.52 0.80 0.35 0.29 0.70 0.27 0.42

193-195 220-222 214-216 216-218 217-219 208-210 248-250 262-264 196-198 175-177 195-197 175-177 198-200

− − − − − − − − − − − − −

0.93 0.83 0.80

258-260 303-305 180-182

− − −

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17 18

O O

H H

CH3(CH2)4CH2

3-NO2C6H4 4-NO2C6H4

4-17 4-18

12 16

66 70

0.70 0.58

219-221 193-195

− −

19

O

H

4-OCH3C6H4

4-CHOC6H4

4-19

12

82

0.37

174-176

−

20 21 22

O O O

H CH3 CH3

4-CF3C6H4 4-S(CH3)C6H4

4-CHOC6H4 3,4-di-OCH3C6H3 9-Anthracenyl

4-20 4-21 4-22

14 16 16

77 80 76

0.45 0.37 0.45

160-162 218-220 254-256

− − −

23

O

CH3

CH3CH2CH2

4-23

16

74

0.50

235-236

−

24

O

CH3

2-FC6H4

4-24

18

62

0.87

104-106

−

25

O

CH3

4-FC6H4

4-25

18

65

0.78

125-126

−

26 27 28 29 30 31 32 33

O O S S S S S S

CH3 CH3 H H H H H H

4-CHOC6H4 4-CHOC6H4 4-OCH3C6H4 2-Furyl 4-BrC6H4 4-NO2C6H4 4-OCH3C6H4 4-OCH3C6H4

4-26 4-27 4-28 4-29 4-30 4-31 4-32 4-33

14 16 14 16 16 15 18 18

69 68 83 75 78 80 67 73

0.60 0.62 0.35 0.48 0.41 0.37 0.63 0.50

172-174 >314 210-212 176-178 194-196 175-177 296-298 201-203

− − − − − − − −

34

S

H

3,4-OCH2OC6H3

4-34

18

74

0.48

210-212

−

4-S(CH3)C6H4 4-CF3C6H4 C6H5 4-CF3C6H4 4-OCF3C6H4 4-S(CF3)C6H4 3,5-di-CF3C6H3

9



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35 36 37 38 39

S S S S S

H H H H H

CH3CH2CH2 CH3CH2CH2 CH2 CH3(CH2)4CH2 c-Hex

2-NO2C6H4 3-NO2C6H4 4-NO2C6H4 (CH3)2CH 2-Naphthyl

4-35 4-36 4-37 4-38 4-39

14 15 14 15 18

76 77 78 74 70

0.48 0.45 0.43 0.53 0.59

178-180 241-243 166-168 201-203 166-168

− − − − −

40 41 42

S S S

H H H

4-OCH3C6H4 4-CF3C6H4 c-Hex

4-CHOC6H4 4-CHOC6H4 4-CHOC6H4

4-40 4-41 4-42

14 16 14

81 72 75

0.37 0.53 0.49

201-203 >330 231-233

− − −

a

Reaction Conditions: barbituric acid/N,N-dimethylbarbituric acid/2-thiobarbituric acid (1; 1.0 mmol), amines (2; 0.5 mmol) and aldehydes (3; 0.5 mmol) in 4 mL of water at room temperature in the absence of any catalyst/additive; bIsolated yields.

10


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With this successful background, we were motivated to study the present protocol whether capable

to

furnish

5,5'-(1,4-phenylene)bis(10-alkyl/aryl-2,8-dioxo/dithioxo-9,10-

dihydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,3H,5H,7H)-dione) scaffold upon reaction with bis-carboxyaldehyde such as phthalaldehyde, isophthalaldehyde and terephthalaldehyde. Accordingly, we performed the reaction between barbituric acid (4 equiv.), an amine (2 equiv.) and bis-carboxyaldehyde (1 equiv.) in aqueous medium at ambient conditions, and observed that both phthalaldehyde and isophthalaldehyde did not undergo any reaction (possibly due to steric crowding), while terephthalaldehyde produced the desired bis-9,10-dihydropyrido[2,3-d:6,5d']dipyrimidine scaffold (4′) satisfactorily. We performed a set of eight such one-pot multicomponent reaction between barbituric acid/N,N-dimethylbarbiturc acid/2-thiobarbituric acid (4 equiv.), substituted aliphatic/aromatic amines (2 equiv.) and terephthalaldehyde (4formylbenzaldehyde; 1 equiv.) in water at room temperature without the aid of any added catalyst. To our delight that in all these eight occasions we were successful in isolating the respective desired products of 5,5'-(1,4-phenylene)bis(10-alkyl/aryl-2,8-dioxo/dithioxo-9,10dihydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,3H,5H,7H)-dione) (4′-1–4′-8) with good yields ranging from 75-83% within 14-18h. The overall results are summarized in Table-3.

All the products (4-1-4-42 and 4′-1-4′-8) were isolated pure just by washing with cold aqueous ethanol. All the isolated products are new and were fully characterized on the basis of their analytical data and detailed spectral studies including FT-IR, 1H NMR, DEPT-135.

11


13

C NMR and


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Page 12 of 39

Table 3 Synthesis of diversely substituted 5,5'-(1,4-phenylene)bis(10-alkyl/aryl-2,8-dioxo/dithioxo-9,10-dihydropyrido[2,3-d:6,5d']dipyrimidine-4,6(1H,3H,5H,7H)-dione) (4′)

Time (h)

Yield (%)a,b E-Factor (g/g)

4′-1

16

83

4-CHOC6H4

4′-2

18

4-CH3C6H4

4-CHOC6H4

4′-3

CH3

4-SCH3C6H4

4-CHOC6H4

O

CH3

4-CF3C6H4

6

S

H

7

S

8

S

Entry Substituent (X)

Substituent (R1)

Substituent (R2)

Substituent (R3)

Product

1

O

H

4-OCH3C6H4

4-CHOC6H4

2

O

H

4-CF3C6H4

3

O

CH3

4

O

5

Melting point ( οC) Found

Reported

0.37

155-157

−

78

0.45

>330

−

14

80

0.41

168-170

−

4′-4

15

82

0.37

155-157

−

4-CHOC6H4

4′-5

18

75

0.49

195-197

−

4-OCH3C6H4

4-CHOC6H4

4′-6

17

82

0.38

280-282

−

H

4-CF3C6H4

4-CHOC6H4

4′-7

18

80

0.40

198-200

−

H

c-Hex

4-CHOC6H4

4′-8

16

81

0.41

232-234

−

a

Reaction Conditions: barbituric acid/N,N-dimethylbarbituric acid/2-thiobarbituric acid (1; 1.0 mmol), amines (2; 0.5 mmol) and aldehydes (3; 0.25 mmol) in 4 mL of water at room temperature in the absence of any catalyst/additive; bIsolated yields.

12


Page 13 of 39

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We herein propose a possible mechanism (Scheme 2) for the water-mediated one-pot synthesis of diversely substituted 5-alkyl/aryl/heteroaryl-10-alkyl/aryl-2,8-dioxo/dithioxo-9,10dihydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,3H,5H,7H)-diones

(4)

from

pseudo-six-

component reaction of barbituric acids (1), amines (2) and aldehydes (3), based on pH monitoring throughout the progress of the reaction as well as isolation and characterization of respective intermediates 7 and 9 for a representative entry (Entry 5, Table 2). We successfully isolated

and

characterized

(see

experimental)

the

enamine

derivative,

6-((4-

bromophenyl)amino)pyrimidine-2,4(1H,3H)-dione (7-5; yield: 77%) from the reaction of barbituric acid (1-5; 1 equiv.) and 4-bromoaniline (2-5; 1 equiv.), and also the chalcone derivative, 4-((2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)methyl)benzonitrile (9-5; yield: 71%) from the reaction of barbituric acid (1-5; 1 equiv.) and 4-cyanobenzaldehyde (3-5; 1 equiv.) in aqueous medium at ambient conditions without the aid of any added catalyst. In the next step, these isolated intermediates 7-5 and 9-5 upon mixing and stirring together in water produced the desired product, 4-(10-(4-bromophenyl)-2,4,6,8-tetraoxo-1,2,3,4,5,6,7,8,9,10decahydropyrido[2,3-d:6,5-d']dipyrimidin-5-yl)benzonitrile (4-5) under the same reaction conditions. The results of pH monitoring throughout the progress of this representative entry 5 are quite logical with the proposed path — the first molecule of barbituric acid (1-5; 0.5 mmol) in 2 mL of distilled water recorded a pH of 2.57 that shifted to 2.93 on addition of 4-bromoaniline (2-5; 0.5 mmol) to it. Such an acidic pH of the reaction mixture facilitates formation of the corresponding imine 6 (6-5) through a condensation reaction between 1-5 and 2-5. The inmine, thus formed, then tautomerizes to enamine 7 (7-5). In another step, the second molecule of barbituric acid (15; 0.5 mmol) in 2 mL of distilled water when added with 4-cyanobenzaldehyde (3-5; 0.5 mmol) recorded a pH of 1.44, and under this acidic condition the equilibrium is shifted towards the enol form (1′), which takes part in the Claisen-Schmidt condensation with the activated aldehyde 3 to generate chalcone 9. Once enamine 7 and chalcone 9 species are formed, they mutually undergo Michael addition to produce the adduct 10, which subsequently tautomerizes to intermediate 11. Under acidic pH of the reaction media, this Michael adduct 11 then takes part in a facile intramolecular ring-closure via 6-exo-trig process to generate the cycloadduct 12 that eventually furnishes the desired product 4 on removal of water as a green waste (Scheme 2). 13



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Page 14 of 39

H

2O

(ta

er om t u

) ism

Scheme 2: Proposed mechanism for the water-mediated pseudo-six-component one-pot synthesis of diversely substituted 2,8-dioxo/dithioxo-9,10-dihydropyrido[2,3-d:6,5d']dipyrimidine-4,6(1H,3H,5H,7H)-diones (4) at ambient conditions We also examined the feasibility of this method for somewhat scaled-up (on the gram scale; 10 mmol scale) experiment with three varying entries (Table 4; entries 1-3) at room temperature in aqueous medium under catalyst-free conditions. All the three varying barbituric acids underwent 10 mmol scale reactions smoothly with three different sets of amines and aldehydes to furnish

the

respective

desired

products,

viz.

5-(4-nitrophenyl)-10-(p-tolyl)-9,10-

dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraone (4-2), 2-(5-(anthracen9-yl)-1,3,7,9-tetramethyl-2,4,6,8-tetraoxo-1,2,3,4,6,7,8,9-octahydropyrido[2,3-d:6,5d']dipyrimidin-10(5H)-yl)propanoic

acid

(4-22),

and

5-(furan-2-yl)-2,8-dithioxo-10-(4-

(trifluoromethyl)phenyl)-2,3,7,8,9,10-hexahydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,5H)dione (4-29), in 88%, 73% and 74% respective isolated yields; the product-yields of these largescale reactions are almost similar with 0.5 mmol scale entry (Table 2, entries 2, 22 and 29) in 14


Page 15 of 39

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terms of respective yield and time. This experimental outcome is quite promising for possible application of this catalyst-free room temperature protocol in large-scale production of such biologically relevant heterocycles. Table 4. Large scale synthesis of a set of three varying 9,10-dihydropyrido[2,3-d:6,5d']dipyrimidine derivatives (4)

Entry 1 2

Substituent (X) O O

Substituent (R1) H CH3

Substituent (R2)

Substituent (R3)

Product

Time (h)

Yield (%)a,b

4-CH3C6H4

4-NO2C6H4 9-Anthracenyl

4-2 4-22

14 18

88 73

3 S H 4-CF3C6H4 2-Furyl 18 74 4-29 Reaction Conditions: barbituric acid/N,N-dimethylbarbituric acid/2-thiobarbituric acid (1; 20 mmol), amines (2; 10 mmol) and aldehydes (3; 10 mmol) in 15 mL of water at room temperature in the absence of any catalyst/additive; b Isolated yields. a

This is also to be mentioned herein that the washings collected upon filtration and purification of isolated products can be reused for individual cases. We performed a representative recycling experiment with such washings obtained during the large-scale synthesis of

5-(4-nitrophenyl)-10-(p-tolyl)-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,

5H, 7H)-tetraone (4-2; Table 4, entry 1) — the collective washings containing the residual reactants and certain portion of the product as washed out with ethanol-water on purification was made an optimum volume of about 15 mL each time (by distilling out ethanol and excess amount of water) to run the next batch of reaction upon adding the requisite reactants [barbituric acid (1; 20 mmol), 4-methylamine (2; 10 mmol) and 4-nitrobenzaldehyde (3; 10 mmol)]. We carried out this representative recycling experiment with this entry (Table 4, entry 1) for four times, and the desired product 4-2 was isolated in almost identical yield (88-91%) in all the runs. 15



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Page 16 of 39

We evaluated green chemistry credentials of this newly developed one-pot synthetic protocol by performing a series of green metrics calculations86−93 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 and water intensity (SI and WI) for all the synthesized compounds 4 (4-1‒4-42) and 4′ (4′-1‒4′-8) (see Supporting Information). The calculated effective mass yield, atom economy and atom efficiency for the method amounts to up to 83.93%, 91.79% and 84.02%, respectively. The calculated carbon efficiency (56.0 to 94.0%) for this process is also quite good. As reaction mass efficiency (RME) includes all reactant mass, yield, and atom economy, it is the most useful metric to determine the greenness of a process. Calculations of RME (51.79 to 83.93%) also indicate excellent green credential of the present method. Similarly, process mass intensity (PMI) evaluation (74.26 to 41.28 g/g) also corroborates with this fact. The calculated E-factors (g/g) are found to be in the range of 0.93 to 0.19, which are indicative of the considerable greenness of this present method; Respective Efactor for each entry is shown in Table 2 and 3. All other parameters have also been found to be in order. Respective data and their calculations for all the entries are given in the Supporting Information. In conclusion, we have developed a simple, catalyst-free and water-mediated, energyefficient, and conveniently practical alternative green method for easy access to a huge range of biologically-interesting diverse and functionalized 5-alkyl/aryl/heteroaryl-10-alkyl/aryl-2,8dioxo/dithioxo-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,3H,5H,7H)-dione derivatives 4 (4-1‒4-42) and 5,5'-(1,4-phenylene)bis(10-alkyl/aryl-2,8-dioxo/dithioxo-9,10dihydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,3H,5H,7H)-dione) 4′ (4′-1‒4′-8) from the onepot pseudo-six component reaction between barbituric/2-thiobarbituric acids (1), substituted amines (2) and aldehydes (3) in aqueous medium at room temperature. The key advantages of this present protocol include mild reaction conditions at room temperature, avoidance of catalyst, use of water as reaction media, operational simplicity and clean reaction profiles, energyefficiency, use of commercially available low-cost starting materials and ease of product isolation/purification without the aid of tedious column chromatography, good to excellent yields, high atom-economy and low E-factor, thereby, satisfying the triple bottom line 16


Page 17 of 39

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philosophy of green and sustainable chemistry.94 Moreover, reusability of the reaction media and the feasibility of gram-scale synthesis are the added advantages to this protocol. The present method satisfies green credentials at the best. Keeping in view of the synthetic importance of such biologically relevant multi-heterocentric organic scaffolds, the present catalyst-free methodology with mild reaction conditions and operational simplicity offers the possibility of its use with cost-effective and environmentally friendlier ways for large-scale syntheses as well.

EXPERIMENTAL SECTION General Considerations. Infrared spectra were recorded using a Shimadzu (FT-IR 8400S) FTIR spectrophotometer using KBr disc. 1H and 13C NMR spectra were collected at 400 MHz and 100 MHz, respectively, on a Bruker DRX spectrometer using CDCl3 and DMSO-d6 as solvents. Elemental analyses were performed with a Perkin Elmer 2400 Series II elemental analyzer instrument. Melting point was recorded on a Chemiline CL-725 melting point apparatus and is uncorrected. Thin Layer Chromatography (TLC) was performed using silica gel 60 F254 (Merck) plates.

General

Procedure

for

the

Synthesis

of

5-alkyl/aryl/heteroaryl-10-alkyl/aryl-2,8-

dioxo/dithioxo-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,3H,5H,7H)-diones (4) and 5,5'-(1,4-phenylene)bis(10-alkyl/aryl-2,8-dioxo/dithioxo-9,10-dihydropyrido[2,3-d:6,5d']dipyrimidine-4,6(1H,3H,5H,7H)-dione) (4′):

A magnetic stir bar, barbituric/N,N-dimethylbarbituric/2-thiobarbituric acid (1; 0.5 mmol), amines (2; 0.5 mmol) and 2 mL distilled water were transferred to an oven-dried reaction tube in a sequential manner at ambient conditions, and the reaction mixture was then stirred for about 1 h. After then, the reaction mixture was added with another portion of barbituric/N,Ndimethylbarbituric/2-thiobarbituric acid (1; 0.5 mmol), aldehydes (3; 0.5 mmol in case of 4 and 0.25 mmol in case of 4′) and 2 mL of distilled water in a sequential manner at ambient conditions. The overall reaction mixture was then stirred vigorously for stipulated time-frame (10-18 h). The progress of the reaction was monitored by TLC. On completion of the reaction, a solid mass precipitated out that was filtered off, followed by purification of the crude product 17



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Page 18 of 39

just by washing with cold aqueous ethanol. The structure of each purified compound (both 4 and 4′) 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 representative compounds (4 and 4′) are given below:

5-(4-Nitrophenyl)-10-phenyl-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H, 5H,7H)-tetraone (4-1). White solid; yield: 85% (190 mg; 0.5 mmol scale); mp = 193-195 οC; IR (KBr): νmax = 3268 (NH), 3124, 3006, 1698 (CONH), 1683 (CONH), 1629, 1618, 1501, 1489, 1471, 1409, 1370, 1345, 1292, 1222, 1157, 1113, 907, 878, 850, 784, 739, 689, 647, 556, 451, 434 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 10.19 (br s, 4H, 4 × -NH), 8.05 (d, 2H, J = 8.8 Hz, Ar-H), 7.39 (t, 2H, J = 8.0 & 7.6 Hz, Ar-H), 7.28 (d, 2H, J = 8.4 Hz, Ar-H), 7.23 (d, 1H, J = 7.6 Hz, Ar-H), 7.19 (dd, 2H, J = 8.0 & 0.8 Hz, Ar-H), 6.05 (s, 1H, -CH) ppm;

13

C NMR (100

MHz, DMSO-d6): δ = 168.47 (CO), 165.01 (CO), 164.93 (CO), 163.26 (CO), 154.65, 151.06 (2C), 145.45, 135.73, 130.08 (2C), 128.34 (2C), 126.04, 123.30 (2C), 121.65 (2C), 90.73 (2C), 31.90 (CH) ppm. Elemental analysis: calcd (%) for C21H14N6O6: C, 56.51; H, 3.16; N, 18.83; Found: C, 56.43; H, 3.15; N, 18.86.

10-(4-Methoxyphenyl)-5-(4-(trifluoromethyl)phenyl)-9,10-dihydropyrido[2,3-d:6,5-d'] dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraone (4-6). White solid; yield: 87% (217 mg; 0.5 mmol scale); mp = 208-210 οC; IR (KBr): νmax = 3195 (NH), 3030, 2943, 2915, 2834, 1717, 1684 (CONH), 1680 (CONH), 1644, 1603, 1507, 1391, 1326, 1258, 1229, 1161, 1119, 1068, 873, 821,653, 582, 551, 460 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 10.11 (br s, 4H, 4 × NH), 7.49 (d, 2H, J = 8.4 Hz, Ar-H), 7.21 (d, 2H,J = 8.0 Hz, Ar-H), 7.15 (dd, 2H, J = 7.2, 2.4 & 2.0 Hz, Ar-H), 6.96 (dd, 2H, J = 7.2, 2.4 & 2.0 Hz, Ar-H), 5.99 (br s, 1H, -CH), 3.73 (s, 3H, ArOCH3) ppm;

13

C NMR (100 MHz, DMSO-d6): δ = 164.42 (2 × CO), 163.89 (2 × CO), 157.92

(2C), 151.10 (2C), 150.69, 129.47, 127.82 (2C), 127.43, 124.80 (CF3), 123.24 (2C), 115.31 (2C), 114.96, 91.06 (2C), 55.89 (Ar-OCH3), 31.31 (CH) ppm. Elemental analysis: calcd (%) for C23H16F3N5O5: C, 55.32; H, 3.23; N, 14.02; Found: C, 55.41; H, 3.25; N, 14.00. 18


Page 19 of 39

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5-(3-Bromophenyl)-10-(3-methoxyphenyl)-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-2, 4,6,8(1H,3H,5H,7H)-tetraone (4-10). Pinkish white solid; yield: 86% (219 mg; 0.5 mmol scale); mp = 175-177 οC; IR (KBr): νmax = 3364 (NH), 3165 (NH), 3123, 3000, 2839, 1711, 1680 (CONH), 1641, 1617, 1580, 1472, 1415, 1368, 1298, 1275, 1231, 1156, 1040, 895, 864, 840, 781, 684, 554, 449 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 10.22 (br s, 4H, 4 × -NH), 7.27 (d, 1H, J = 8.4 Hz, Ar-H), 7.23 (d, 1H, J = 9.2 Hz, Ar-H), 7.14 (br s, 1H, Ar-H), 7.12-7.10 (m, 1H, Ar-H), 7.02 (d, 1H, J = 7.6 Hz, Ar-H), 6.74 (dd, 1H, J = 8.0, 2.4 & 1.6 Hz, Ar-H), 6.72-6.71 (m, 1H, Ar-H), 6.69-6.67 (m, 1H, Ar-H), 5.89 (s, 1H, -CH), 3.72 (s, 3H, Ar-OCH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 168.39 (2 × CO), 165.44 (2 × CO), 160.64,151.17, 148.28, 138.16, 131.10, 130.33, 129.83, 128.07, 126.50, 124.99, 121.77, 113.36, 110.76, 106.94, 90.67, 79.70, 55.79 (Ar-OCH3), 31.37 (CH) ppm. Elemental analysis: calcd (%) for C22H16BrN5O5: C, 51.78; H, 3.16; N, 13.72; Found: C, 51.81; H, 3.15; N, 13.79.

10-(4-(Trifluoromethyl)phenyl)-5-(3,4,5-trimethoxyphenyl)-9,10-dihydropyrido[2,3-d:6,5d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraone (4-14). Yellow solid; yield: 57% (159 mg; 0.5 mmol scale); mp = 258-260 οC; IR (KBr): νmax = 3239 (NH), 3013, 2944, 2836, 1659 (CONH), 1578, 1548, 1503, 1455, 1413, 1361, 1305, 1255, 1188, 1160, 1128, 995, 866, 788, 758, 675, 615, 508 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 11.38 (br s, 1H, -NH), 11.24 (br s, 1H, NH), 11.13 (br s, 2H, 2 × -NH), 8.26 (d, 1H, J = 6.0 Hz, Ar-H), 7.83 (d, 2H, J = 6.0 Hz, Ar-H), 7.31 (d, 1H, J = 6.8 Hz, Ar-H), 6.66 (d, 2H, J = 7.2 Hz, Ar-H), 6.42 (br s, 1H, -CH), 3.83 (s, 3H, Ar-OCH3), 3.82 (s, 3H, Ar-OCH3), 3.80 (s, 3H, Ar-OCH3) ppm;

13

C NMR (100 MHz, DMSO-

d6): δ = 168.22 (2 × CO), 164.20 (2 × CO), 162.56, 155.69, 152.63, 152.54, 152.42, 152.23, 152.12, 150.60, 142.42, 128.00, 126.71 (2C), 117.74, 113.77 (2C), 113.03 (2C), 60.76 (ArOCH3), 60.39 (Ar-OCH3), 56.48 (Ar-OCH3), 32.31 (CH) ppm. Elemental analysis: calcd (%) for C25H20F3N5O7: C, 53.67; H, 3.60; N, 12.52; Found: C, 53.70; H, 3.59; N, 12.49.

3-(4-Hydroxyphenyl)-2-(5-(4-nitrophenyl)-2,4,6,8-tetraoxo-1,2,3,4,6,7,8,9-octahydropyrido [2,3-d:6,5-d']dipyrimidin-10(5H)-yl)propanoic acid (4-18). White solid; yield: 70% (187 mg; 0.5 mmol scale); mp = 193-195 οC; IR (KBr): νmax = 3373 (OH), 3203 (NH), 3136, 3016, 2936, 19



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Page 20 of 39

2900, 2871, 1709 (COOH), 1680 (CONH), 1630, 1589, 1510, 1455, 1349, 1284, 1220, 1108, 1043, 928, 851, 776, 733, 663, 581, 540, 530, 434 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 10.14 (br s, 4H, 4 × -NH), 9.38 (br s, 1H, Ar-OH),8.06 (d, 2H, J = 8.8 Hz, Ar-H), 7.27 (d, 2H, J = 8.4 Hz, Ar-H), 7.04 (d, 2H, J = 8.4 Hz, Ar-H), 6.71 (d, 2H, J = 8.4 Hz, Ar-H), 6.07 (s, 1H, CH), 4.09 (t, 1H, J = 6.4 & 6.0 Hz, -CH(COOH)CH2-), 2.99-2.96 (m, 2H, -CH2-) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 171.20 (COOH), 157.21 (2 × CO), 155.08(2 × CO), 151.26 (2C), 145.53 (2C), 131.09 (2C), 128.45 (2C), 125.25 (2C), 123.44 (2C), 115.99 (2C), 91.04 (2C), 54.07 (CH(COOH)), 35.69 (CH), 31.88 (CH2) ppm. Elemental analysis: calcd (%) for C24H18N6O9: C, 53.94; H, 3.39; N, 15.73; Found: C, 53.88; H, 3.40; N, 15.77. 4-(2,4,6,8-Tetraoxo-10-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8,9,10-decahydropyrido [2,3-d:6,5-d']dipyrimidin-5-yl)benzaldehyde (4-20). Yellow solid; yield: 77% (191 mg; 0.5 mmol scale); mp = 160-162 οC; IR (KBr): νmax = 3204 (NH), 3097, 2853, 1701 (CHO), 1679 (CONH), 1578, 1445, 1412, 1337, 1305, 1217, 1168, 1121, 1068, 1019, 982, 814, 688, 640, 593, 546, 521, 456 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 11.46 (s, 2H, 2 × -NH), 11.31 (s, 2H, 2 × -NH), 10.47 (br s, 1H, -CHO), 8.32-8.24 (m, 2H, Ar-H), 8.06 (br s, 2H, Ar-H), 7.32 (d, 2H, J = 8.8 Hz, Ar-H), 6.67 (d, 2H, J = 8.8 Hz, Ar-H), 5.90 (br s, 1H, -CH) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 193.28 (CHO), 163.63 (2 × CO), 161.93 (2 × CO), 153.47 (2C), 152.16, 150.67 (2C), 136.20, 132.59, 132.36 (2C), 129.07, 126.73 (2C), 126.69 (2C), 120.97 (2C), 113.80 (CF3), 32.45 (CH) ppm. Elemental analysis: calcd (%) for C23H14F3N5O5: C, 55.54; H, 2.84; N, 14.08; Found: C, 55.51; H, 2.83; N, 14.10.

5-(4-Fluorophenyl)-1,3,7,9-tetramethyl-10-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro2H-pyran-3-yl)-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)tetraone (4-25). White solid; yield: 65% (183 mg; 0.5 mmol scale); mp = 125-126 οC;IR (KBr): νmax = 3440-3360 (OH), 3072, 3001, 2963, 2930, 2849, 1692 (CONCH3), 1665 (CONCH3), 1513, 1453, 1423, 1376, 1276, 1227, 1136, 1093, 1041, 984, 841, 790, 756, 639, 597, 520, 469, 451 cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.45-7.42 (m, 1H, Ar-H), 7.15-7.11 (m, 1H, Ar-H), 7.02-6.97 (m, 2H, Ar-H), 5.59 (s, 1H, -CH), 4.38 (t, 1H, J = 7.2 & 6.8 Hz, -CH(CH2OH)), 4.29 (d, 2H, J = 6.4 Hz, -CH(CH2OH)), 3.48 (br s, 1H, -OH), 3.44 (s, 4H, 4 × -CH(OH)), 3.42 (br s, 20


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1H, -OH), 3.38 (br s, 1H, -OH), 3.36 (s, 6H, 2 × -NCH3), 3.31 (br s, 1H, -OH), 3.24 (s, 3H, NCH3), 3.19 (s, 3H, -NCH3) ppm; 13C NMR (100 MHz, CDCl3): δ = 167.80 (CO), 166.79 (CO), 164.70 (CO), 163.35 (CO), 150.56, 136.85, 131.14, 128.18, 128.09, 115.50, 115.48, 115.27, 93.42 (2C), 51.25 (4 × CH(OH)), 45.75(N-CH), 34.04(CH2(OH)), 31.07(CH), 29.47 (NCH3), 29.15 (NCH3), 28.99 (NCH3), 28.89 (NCH3) ppm. Elemental analysis: calcd (%) for C25H28FN5O9: C, 53.47; H, 5.03; N, 12.47; Found: C, 53.52; H, 5.01; N, 12.44.

4-(1,3,7,9-Tetramethyl-10-(4-(methylthio)phenyl)-2,4,6,8-tetraoxo-1,2,3,4,5,6,7,8,9,10decahydropyrido[2,3-d:6,5-d']dipyrimidin-5-yl)benzaldehyde (4-26). Yellow solid; yield: 69% (183 mg; 0.5 mmol scale); mp = 172-174 οC;IR (KBr): νmax = 3078, 2954, 1680 (CHO & CONCH3), 1583, 1573, 1432, 1379, 1306, 1257, 1152, 1090, 962, 881, 835, 798, 751, 638, 552, 511, 484, 442 cm−1;1H NMR (400 MHz, CDCl3): δ = 10.08 (s, 1H, -CHO), 8.58-8.52 (m, 1H, Ar-H), 8.12 (d, 1H, J = 8.4 Hz, Ar-H), 8.07-8.02 (m, 1H, Ar-H), 7.99-7.98 (m, 1H, Ar-H), 7.30 (d, 1H, J = 8.4 Hz, Ar-H), 7.22 (dd, 1H, J = 8.4, 2.8 & 2.4 Hz, Ar-H), 7.17 (dd, 1H, J = 6.8, 2.0 & 0.8 Hz, Ar-H), 6.63 (d, 1H, J = 8.8 Hz, Ar-H), 4.78 (br s, 1H, -CH), 3.43 (s, 3H, -NCH3), 3.38-3.35 (m, 3H, -NCH3), 3.31 (s, 3H, -NCH3), 2.51 (s, 3H, -NCH3), 2.41 (s, 3H, -SCH3) ppm; 13

C NMR (100 MHz, CDCl3): δ = 191.92 (CHO), 164.86 (CO), 158.11 (CO), 157.98 (CO),

157.35 (CO), 133.72, 132.35, 131.18 (2C), 130.19, 129.32, 129.23, 128.42, 127.67, 127.59, 127.55, 121.85, 121.82, 121.79, 115.93 (2C), 39.53 (2 × NCH3), 29.30 (CH), 28.64 (2 × NCH3), 18.91 (SCH3) ppm. Elemental analysis: calcd (%) for C27H25N5O5S: C, 61.00; H, 4.74; N, 13.17; Found: C, 60.92; H, 4.72; N, 13.20.

5-(4-Bromophenyl)-2,8-dithioxo-10-(4-(trifluoromethoxy)phenyl)-2,3,7,8,9,10-hexahydro pyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,5H)-dione (4-30). White solid; yield: 78% (232 mg; 0.5 mmol scale); mp= 194-196 οC; IR (KBr): νmax = 3101 (NH), 3010, 2920, 2899, 1665 (CONH), 1637, 1630, 1619, 1553, 1431, 1378 (C=S), 1300, 1263 (C=S), 1220, 1171, 1137, 1006, 928, 868, 829, 785, 676, 611, 582, 553, 528, 420 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 11.63 (br s, 4H, 4 × -NH), 7.36-7.32 (m, 4H, Ar-H), 7.21 (dd, 2H, J = 7.6 & 2.0 Hz, Ar-H), 6.94 (dd, 2H, J = 8.4, 1.2 & 0.8 Hz, Ar-H), 5.91 (s, 1H, -CH) ppm; 13C NMR (100 MHz, DMSOd6): δ = 173.36 (2 × CS), 163.49 (CO), 163.43 (CO), 152.63, 143.10 (2C), 136.90, 130.93 21



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(OCF3), 129.37 (2C), 122.82 (3C), 122.37 (2C), 119.32, 118.22 (2C), 95.92 (2C), 30.66 (CH) ppm. Elemental analysis: calcd (%) for C22H13BrF3N5O3S2: C, 44.31; H, 2.20; N, 11.74; Found: C, 44.37; H, 2.19; N, 11.79.

5-(Benzo[d][1,3]dioxol-5-yl)-10-(4-(4-chlorophenoxy)phenyl)-2,8-dithioxo-2,3,7,8,9,10-hexa hydropyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,5H)-dione (4-34). Golden yellow solid; yield: 74% (223 mg; 0.5 mmol scale); mp = 210-212 οC; IR (KBr): νmax = 3205 (NH), 3170, 2892, 1678 (CONH), 1618, 1510, 1487, 1455, 1394, 1318 (C=S), 1296, 1273 (C=S), 1254, 1210, 1184, 1157, 1035, 929, 885, 797, 664, 602, 527, 493 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 11.60 (br s, 4H, 4 × -NH), 7.47-7.37 (m, 4H, Ar-H), 7.13-7.07 (m, 4H, Ar-H), 6.69 (br s, 1H, Ar-H), 6.49 (br s, 2H, Ar-H), 6.20 (br s, 1H, -CH), 5.91 (br s, 2H, -OCH2O-) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 173.19 (2 × CS), 163.54 (CO), 163.47 (CO), 156.03, 155.58, 147.32, 145.08, 137.46, 130.47 (2C), 128.21 (2C), 125.12 (2C), 121.00 (2C), 120.09 (2C), 119.66 (2C), 107.85, 107.53 (2C), 100.88 (OCH2O), 96.39 (2C), 30.66 (CH) ppm. Elemental analysis: calcd (%) for C28H18ClN5O5S2: C, 55.67; H, 3.00; N, 11.59; Found: C, 55.74; H, 3.01; N, 11.62.

10-Cyclohexyl-5-isopropyl-2,8-dithioxo-2,3,7,8,9,10-hexahydropyrido[2,3-d:6,5-d'] dipyrimidine-4,6(1H,5H)-dione (4-38). White solid; yield: 74% (150 mg; 0.5 mmol scale); mp = 201-203 οC; IR (KBr): νmax = 3180 (NH), 3109, 3089, 2953, 2865, 1662 (CONH), 1629, 1596, 1520, 1446, 1352 (C=S), 1298, 1238 (C=S), 1192, 1139, 1013, 866, 754, 621, 555, 504, 453 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 11.46 (br s, 2H, 2 × -NH), 11.23 (br s, 2H, 2 × -NH), 4.18 (d, 1H, J = 11.6 Hz, -CH), 2.99-2.96 (m, 1H, N(-CH)), 1.89-1.87 (m, 2H, -CH2-), 1.72-1.68 (m, 2H, -CH2-), 1.59-1.57 (m, 1H, -CH), 1.31-1.07 (m, 6H, 3 × -CH2-), 0.71 (d, 6H, J = 6.8 Hz, 2 × -CH3) ppm;

13

C NMR (100 MHz, DMSO-d6): δ = 172.74 (2 × CS), 164.09 (2 × CO), 162.39

(2C), 96.58 (2C), 49.83 (N-CH), 34.09 (CH), 30.81 (2 × CH2), 26.50 (CH(CH3)2), 25.00 (2 × CH2), 24.20 (2 × CH3), 21.83 (CH2) ppm. Elemental analysis: calcd (%) for C18H23N5O2S2: C, 53.31; H, 5.72; N, 17.27; Found: C, 53.27; H, 5.70; N, 17.21.

2-(5-(Naphthalen-2-yl)-4,6-dioxo-2,8-dithioxo-1,2,3,4,6,7,8,9-octahydropyrido[2,3-d:6,5-d'] dipyrimidin-10(5H)-yl)propanoic acid (4-39). White solid; yield: 70% (168 mg; 0.5 mmol 22


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scale); mp = 166-168 οC; IR (KBr): νmax = 3360 (OH), 3204 (NH), 3040, 2967, 2899, 2834, 1741,1709 (COOH), 1641 (CONH), 1519, 1463, 1370 (C=S), 1328, 1245 (C=S), 1155, 1104, 1041, 981, 925, 865, 855, 760, 685, 648,585, 534 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 9.91 (s, 2H, 2 × -NH), 9.77 (s, 2H, 2 × -NH), 9.37 (br s, 1H, Ar-H), 8.16 (br s, 2H, Ar-H), 7.05 (d, 2H, J = 8.4 Hz, Ar-H), 6.71 (d, 2H, J = 8.4 Hz, Ar-H), 4.15-4.12 (m, 1H, -CH), 4.09-4.07 (m, 1H, -CH(CH3)), 0.71 (d, 3H, J = 6.4 Hz, -CH3) ppm;

13

C NMR (100 MHz, DMSO-d6): δ =

171.16 (2 × CS), 169.44 (-COOH), 166.18 (2 × CO), 163.52 (2C), 162.76, 157.06, 151.09 (2C), 130.96 (2C), 125.19, 119.69, 115.85 (2C), 91.69 (2C), 54.00 (N-CH), 35.58 (CH), 22.04 (CH3) ppm. Elemental analysis: calcd (%) for C22H17N5O4S2: C, 55.10; H, 3.57; N, 14.60; Found: C, 54.94; H, 3.56; N, 14.57.

4-(10-(4-Methoxyphenyl)-4,6-dioxo-2,8-dithioxo-1,2,3,4,5,6,7,8,9,10-decahydropyrido[2,3-d: 6,5-d']dipyrimidin-5-yl)benzaldehyde (4-40). Whitish grey solid; yield: 81% (199 mg; 0.5 mmol scale);mp = 201-203 οC; IR (KBr): νmax = 3120 (NH), 3074, 2886, 1686 (CONH), 1638, 1602, 1544, 1509, 1441, 1376 (C=S), 1302, 1256 (C=S), 1218, 1171, 1137, 1033, 1009, 926, 874, 827, 771, 673, 611, 554, 509, 431 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 11.63 (br s, 4H, 4 × -NH), 9.89 (s, 1H, -CHO), 7.72 (d, 2H, J = 8.0 Hz, Ar-H), 7.28 (dd, 2H, J = 6.4 & 2.0 Hz, Ar-H), 7.21 (d, 2H, J = 8.4 Hz, Ar-H), 7.03 (dd, 2H, J = 7.2 & 2.0 Hz, Ar-H), 6.04 (s, 1H, CH), 3.75 (s, 3H, Ar-OCH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 193.12 (CHO), 173.57 (2 × CS), 159.47 (2 × CO), 151.83, 134.31, 130.50, 129.87, 128.06, 127.89, 125.05 (2C), 124.37, 123.14, 115.52 (2C), 115.30, 115.11, 95.99 (2C), 56.07 (Ar-OCH3), 31.76(CH) ppm. Elemental analysis: calcd (%) for C23H17N5O4S2: C, 56.20; H, 3.49; N, 14.25; Found: C, 56.27; H, 3.47; N, 14.22.

5,5'-(1,4-Phenylene)bis(10-(4-methoxyphenyl)-9,10-dihydropyrido[2,3-d:6,5-d'] dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraone) (4′-1). Grey solid; yield: 83% (163 mg; 0.25 mmol scale); mp = 155-157 οC; IR (KBr): νmax = 3160 (NH), 3081, 2912, 1699 (CONH), 1673 (CONH), 1668, 1615, 1584, 1511, 1440, 1379, 1307, 1252, 1211, 1175, 1122, 1067, 1023, 954, 824, 799, 740, 637, 508, 433 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 11.12 (br s, 2H, 2 × NH), 10.09 (br s, 6H, 6 × -NH), 8.05 (d, 1H, J = 8.4 Hz, Ar-H), 7.24 (d, 1H, J = 8.8 Hz, Ar-H), 23



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Page 24 of 39

7.14-7.06 (m, 4H, Ar-H), 6.91 (dd, 4H, J = 8.2 & 0.4 Hz, Ar-H), 6.77-7.68 (br s, 2H, Ar-H), 6.01 (br s, 1H, -CH), 5.82 (br s, 1H, -CH), 3.71 (s, 6H, 2 × Ar-OCH3) ppm;

13

C NMR (100 MHz,

DMSO-d6): δ = 168.38 (4 × CO), 164.28 (2 × CO), 157.12 (2 × CO), 152.27 (2C), 151.26, 151.23 (2C), 150.78, 140.91 (2C), 134.59, 127.24 (2C), 126.32 (2C), 124.52, 122.84 (2C), 122.43 (2C), 122.30, 115.39 (4C), 114.98, 91.16 (2C), 56.01 (2 × Ar-OCH3), 31.92 (2 × CH) ppm. Elemental analysis: calcd (%) for C38H28N10O10: C, 58.16; H, 3.60; N, 17.85; Found: C, 58.12; H, 3.61; N, 17.83.

5,5'-(1,4-Phenylene)bis(1,3,7,9-tetramethyl-10-(4-(methylthio)phenyl)-9,10-dihydropyrido [2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraone) (4′-4). Pale yellow solid; yield: 82% (190 mg; 0.25 mmol scale);mp = 155-157οC; IR (KBr): νmax = 3078, 3007, 1695 (CONCH3), 1675 (CONCH3), 1615, 1581, 1570, 1494, 1467, 1435, 1375, 1306, 1255, 1208, 1119, 1068, 950, 922, 800, 753, 741, 720, 637, 580, 509, 431, 425 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 8.01 (d, 2H, J = 8.4 Hz, Ar-H), 7.22 (dd, 4H, J = 6.6, 2.0 & 1.6 Hz, Ar-H), 7.16 (d, 2H, J = 8.0 Hz, Ar-H), 6.94 (d, 4H, J = 8.4 Hz, Ar-H), 6.31 (br s, 2H, 2 × -CH), 3.16 (s, 12H, 4 × -NCH3), 3.11 (s, 12H, 4 × -NCH3), 2.41 (s, 6H, 2 × -SCH3) ppm;

13

C NMR (100 MHz,

DMSO-d6): δ = 166.53 (4 × CO), 163.23 (2 × CO), 163.14 (2 × CO), 151.97 (3C), 151.74 (3C), 134.31 (3C), 129.79 (3C), 129.33 (4C), 127.29 (4C), 119.94 (4C), 91.27 (2C), 29.21 (2 × CH),28.59 (4 × NCH3), 28.38 (4 × NCH3), 17.02 (2 × SCH3) ppm. Elemental analysis: calcd (%) for C46H44N10O8S2: C, 59.47; H, 4.77; N, 15.08; Found: C, 59.52; H, 4.78; N, 15.10.

5,5'-(1,4-Phenylene)bis(2,8-dithioxo-10-(4-(trifluoromethyl)phenyl)-2,3,7,8,9,10-hexahydro pyrido[2,3-d:6,5-d']dipyrimidine-4,6(1H,5H)-dione) (4′-7). Whitish orange solid; yield: 80% (185 mg; 0.25 mmol scale); mp= 198-200οC; IR (KBr): νmax = 3150 (NH), 3055, 2879, 1636 (CONH), 1630, 1619, 1544, 1432, 1371 (C=S), 1324, 1226 (C=S), 1201, 1176, 1138, 1068, 1014, 869, 834, 770, 750, 536, 501, 438 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 11.76 (br s, 8H, 8 × -NH), 7.39 (d, 4H, J = 8.4 Hz, Ar-H), 6.80 (d, 6H, J = 4.0 Hz, Ar-H), 6.78 (s, 2H, Ar-H), 5.83 (s, 2H, 2 × -CH) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 173.33 (4 × CS), 163.61 (4 × CO), 162.78 (2C), 150.17, 139.09 (2C), 132.03, 126.97 (4C), 126.93 (4C), 126.52 (2 × CF3), 24


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124.39 (4C), 115.51 (4C), 96.68 (4C), 30.92 (2 × CH) ppm. Elemental analysis: calcd (%) for C38H22F6N10O4S4: C, 49.35; H, 2.40; N, 15.14; Found: C, 49.39; H, 2.39; N, 15.11.

Isolation and characterization of a representative enamine intermediate [6-((4bromophenyl)amino)pyrimidine-2,4(1H,3H)-dione] 7-5. An oven-dried sealed tube was charged with a magnetic stir bar, barbituric acid (1-5; 0.5 mmol), 4-bromoaniline (2-5; 0.5 mmol) and 2 mL of distilled water in a sequential manner at ambient conditions, and the reaction mixture was then stirred for 15 h. The progress of the reaction was monitored by TLC. On completion of reaction, a white solid mass precipitated out which was filtered

off

and

washed

with

cold

aqueous

ethanol

to

obtain

pure

6-((4-

bromophenyl)amino)pyrimidine-2,4(1H,3H)-dione(7-5): Yield: 77% (109 mg; 0.5 mmol scale); mp 171-173 οC; IR (KBr): νmax = 3117 (NH), 3045, 2983, 2829, 1697 and 1687 (CONH), 1609, 1585, 1480, 1403, 1370, 1286, 1207, 1165, 1077, 1015, 879, 834, 810, 786, 686, 632, 535, 487 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 11.11 (s, 2H, 2 × -NH), 7.12 (d, 2H, J = 8.8 Hz, ArH), 6.51 (d, 2H, J = 8.8 Hz, Ar-H), 5.33 (br s, 1H, vinylic H), 3.46 (s, 1H, -NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 168.21 (2 × CO), 152.10, 148.48 (2C), 131.77 (2C), 116.25 (2C), 106.51 ppm. Elemental analysis: calcd (%) for C10H8BrN3O2: C, 42.58; H, 2.86; N, 14.90; Found: C, 42.52; H, 2.87; N, 14.87.

Isolation and characterization of a representative chalcone intermediate [4-((2,4,6trioxotetrahydropyrimidin-5(2H)-ylidene)methyl)benzonitrile] 9-5. An oven-dried sealed tube was charged with a magnetic stir bar, barbituric acid (1-5; 0.5 mmol), 4-cyanobenzaldehyde (3-5; 0.5 mmol) and 2 mL of distilled water in a sequential manner at ambient conditions, and the reaction mixture was then stirred for 12 h. The progress of the reaction was monitored by TLC. On completion of reaction, a white solid mass precipitated out which was filtered off and washed with cold aqueous ethanol to obtain pure 4-((2,4,6trioxotetrahydropyrimidin-5(2H)-ylidene)methyl)benzonitrile (9-5): Yield: 71% (86 mg; 0.5 mmol scale); mp 223-225 οC; IR (KBr): νmax = 3224 (NH), 3060, 2845, 2232 (CN), 1703-1667 (CONH), 1643 (C=C), 1581, 1579, 1548, 1445, 1408, 1342, 1314, 1291, 1217, 1202, 1117, 25



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Page 26 of 39

1075, 1027, 986, 965, 849, 804, 738, 681, 656, 633, 557, 521, 465, 428 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 11.47 (br s, 1H, -NH), 11.29 (br s, 1H, -NH), 8.28 (s, 1H, vinylic H), 7.99 (d, 2H, J = 8.4 Hz, Ar-H), 7.89 (d, 2H, J = 8.0 Hz, Ar-H) ppm;

13

C NMR (100 MHz, DMSO-

d6): δ = 163.22 (CO), 161.65 (CO), 152.15 (CO), 150.65, 138.39, 132.40 (2C), 131.99 (2C), 122.34, 118.99 (CN), 113.15 ppm. Elemental analysis: calcd (%) for C12H7N3O3: C, 59.75; H, 2.93; N, 17.42; Found: C, 59.80; H, 2.92; N, 17.44.

ASSOCIATED CONTENT Supporting Information Spectral and analytical data along with scanned copies of respective 1H NMR and

13

C NMR

spectra for all the synthesized compounds (4-1–4-42 and 4′-1–4′-8) along with those for enamine (7-5) and chalcone (9-5) intermediates are supplemented. Working formulas for calculations of green metrics and respective calculated data for all the synthesized compounds are also documented in the Supporting Information.

AUTHOR INFORMATION Corresponding Author Prof. (Dr.) Goutam Brahmachari *

E-mail: [email protected]; [email protected]

ORCID Goutam Brahmachari: 0000-0001-9925-6281 Notes The authors declare no competing financial interest

ACKNOWLEDGEMENTS This paper is dedicated to Professor Asit K. Chakraborti on the occasion of his 63rd birthday. Financial support (Grant No. EMR/2014/001220) from the Science and Engineering Research 26


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Board (SERB), Department of Science & Technology (DST), Government of India, New Delhi is gratefully acknowledged. IK is thankful to the UGC, New Delhi for awarding him junior research fellowship. The authors are also thankful to DST-FIST Program, and Department of Chemistry, Visva-Bharati University for infrastructural facilities.

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GRAPHICAL ABSTRACT

Synopsis Water ‒ a powerful reaction media: A catalyst-free alternative green synthetic protocol for functionalized pyrido[2,3-d:6,5-d']dipyrimidines has been developed under ambient conditions.

Green aspects of the process 1. Synthesis of a new series of biologically interesting heterocycles via a newly developed advanced synthetic protocol 2. Use of water as the green solvent 3. Use of no catalyst — self catalysis (reactants) in water medium is the driving force as we elaborated in the mechanistic aspect. 4. No tedious column chromatography was required for purification of synthesized compounds; simple filtration followed by washing with aqueous ethanol warrants a practical method. 5. No heating/refluxing/use of MWI or US — application of just ambient conditions (room temperature and pressure) 6. The protocol can be used for large scale synthesis (gram scale) 7. Practically no waste (water is a green waste) and the filtrate can be reused for several times. 8. Excellent green chemistry credentials 38


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TOC


Development of a Water-Mediated and Catalyst-Free Green Protocol

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