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Ultrasound-Promoted Expedient and Green Synthesis of Diversely Functionalized 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl) (aryl)methyl)pyrimidine-2,4(1H,3H)-diones via One-Pot Multicomponent Reaction under Sulfamic Acid Catalysis at Ambient Conditions Goutam Brahmachari, Mullicka Mandal, Indrajit Karmakar, Khondekar Nurjamal, and Bhagirath Mandal ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.9b00133 • Publication Date (Web): 18 Feb 2019 Downloaded from http://pubs.acs.org on February 18, 2019

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ACS Sustainable Chemistry & Engineering

Sc-2019-00133.R3 Research Article

Ultrasound-Promoted Expedient and Green Synthesis of Diversely Functionalized 6Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(aryl)methyl)pyrimidine-2,4(1H,3H)diones via One-Pot Multicomponent Reaction under Sulfamic Acid Catalysis at Ambient Conditions

Goutam Brahmachari*, Mullicka Mandal, Indrajit Karmakar, Khondekar Nurjamal, Bhagirath Mandal Laboratory of Natural Products & Organic Synthesis, Department of Chemistry, Visva-Bharati (a Central University), Santiniketan-731 235, West Bengal, India. *Corresponding author: Prof. Dr. Goutam Brahmachari (http://orcid.org/0000-0001-9925-6281) E-mail:[email protected]; [email protected] __________________________________________________________________________________

ABSTRACT Development of an ultrasound-promoted green protocol to access pharmaceutically relevant functionalized coumarin-uracil molecular hybrids, 6-amino-5-((4-hydroxy-2-oxo-2H-chromen-3yl)(aryl)methyl)pyrimidine-2,4(1H,3H)-diones (4/4′), has been accomplished based on a threecomponent tandem reaction between 4-hydroxycoumarin (1), substituted aromatic aldehydes (2), and 6-aminouracils (3)/6-amino-2-thiouracil (3′) under sulfamic acid-catalysis in aqueous ethanol. Metalfree one-pot synthesis, rapid reaction-rate with good to excellent yields, use of cost-effective and ecofriendly catalyst and solvent, energy efficiency, easy isolation of products without the need of column chromatographic purification, reusability of reaction media, large-scale synthetic applicability, and excellent green credential parameters of the process, are the salient features of this newly developed method.

___________________________________________________________________________ Keywords: Ultrasound; Sulfamic acid; One-pot multicomponent reaction; Green synthesis; Molecular hybridization; Functionalized coumarin-uracil molecular hybrids

INTRODUCTION Coumarins represent an important class of O-heterocycles of pharmaceutical promise.1-3 This moiety is found to form the basic structural architecture of a handful of effective antibiotic drugs.4,5 1

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Coumarins, both natural and synthetic analogs, have been evaluated to exhibit significant therapeutic potential in treating a diverse range disease manifestations such as oxidative stress,6 blood coagulation,7 cancerous symptoms,8-11 tuberculosis,12 inflammations,13 AIDS14, Alzheimer’s15, and many others.16,17At the same time, pyrimidines belonging to a promising class of N-heterocycles, have drawn keen attention of the chemists and pharmacologists for their potential therapeutic applications.18,19 Categorically, 6-aminouracil and its derivatives offer key structural unit in a vast number of natural and synthetic molecules of potential pharmacological applications,20-24 and also serve as a versatile building block for a good number of purine- and pyrimidine-based marketed drugs.25-27

Threading

of

these

two

therapeutically

promising

scaffolds,

coumarins

and

uracils/thiouracil, following the concept of molecular hybridization (MH)28,29 with a view to construct a new molecular framework anticipating to attain somewhat extended biological profiles, thus finds logical. Figure 1 represents a glimpse of some of the natural and synthetic coumarin-pyrimidine molecular scaffolds of potential interest.30-44 Br OH O O

O

O O

OH

I: Bromadiolone: anticoagulant (vitamin K antagonist)[30,31]

O

H3C

O

O

N N

O

HN O

OH O

R

V: Warfarin (R = H) VI: Acenocoumarol (R = NO2)[37] (anticancer,[38] anticoagulant,[39] anti-inflammatory,[40] arthritis,[41] antithrombosis[42])

CH3

N O

O HO

N

Cl

NH

N O H IV: Uramustine (antineoplastic)[36]

CH3 N N

CH3 N

O

N O

III: Caffeine (antimicrobial)[34,35]

O

R

N

N CH3

II: Carbochromen (potent drug for estimation of coronary dilatory capacity)[32,33]

CH3 OH

N

N

O

Cl

CH3

O

N

O

OH

O

CH3 VII: R = CH3; VIII: R = Cl (antimicrobial)[43]

H3C IX: MCK-442 (anti-HIV)[44]

CH3

N

O O

O HO

N

O

CH3

X (anti-biofilm activity)[43]

Figure 1. Examples of pharmacologically useful coumarin-pyrimidine molecular scaffolds of natural and synthetic origins.30-44 Literature survey revealed one previous report45 on the synthesis of such coumarin-pyrimidine molecular scaffold from the reaction between coumarin, aldehydes and N,N-dimethyl-6-aminouracil in refluxing ethanol using L-proline as catalyst. However, the scope of this method is very limited — only a set of seven such compounds were synthesized under heating condition requiring up to 10 h. As part of our ongoing endeavors in designing green synthetic methods46-54 for biologically promising organic molecules, we thus felt pertinent to develop an alternative protocol for the preparation of these coumarin-pyrimidine conjugates with enhanced synthetic scope and better reaction profiles, thereby satisfying several green chemistry aspects. Accordingly, we herein report an ultrasoundpromoted expedient and green practical method to access functionalized 6-amino-5-((4-hydroxy-22


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oxo-2H-chromen-3-yl)(aryl)methyl)pyrimidine-2,4(1H,3H)-diones

(4/4′)

from

the

one-pot

multicomponent reaction between 4-hydroxycoumarin (1), substituted aromatic aldehydes (2) and 6aminouracils (3)/ 6-amino-2-thiouracil (3′) under sulfamic acid catalysisin aqueous ethanol (1:1) at ambient conditions (28-30 C); the overall results are outlined in Scheme 1. The notable advantages of this present protocol compared to the earlier method are broader substrate scope, reduced reaction time in minutes, energy-efficiency occurring at ambient temperature, use of aqueous ethanol as solvent, reusability of reaction media, large-scale synthetic applicability, high atom-economy and low E-factor, and high turnover number. During the recent past, ultrasound irradiation has been in wide use as a green tool in organic transformations due to its several benefits such as enhancement of reaction rates, energy savings, and the enhancement in the mass transfer and product selectivity.55-59 The use of aqueous ethanol as green solvent,60-62 metal-free synthesis,63-65 effective application of ultrasonication in expediting reaction rate,66,67 and beneficial application of one-pot multicomponent reaction (MCR) strategy,

68-72

and

ambient reaction conditions73-75 are, thus, the steps forward to the cause of green and sustainable chemistry. O N

N O R2 6-Aminouracil (3, 0.25 mmol)

H2N

OH

CHO +

O

O

4-Hydroxycoumarin (1, 0.25 mmol)

1

R

Ultrasound irradiation (US) at ambient conditions for 10-30 min Substituted aldehydes (130 W, 20 kHz at 40% amplitude) (2, 0.25 mmol) (no column chromatography)

R = H; 3-Br; 4-F; 4-CN; 4-CF3; 3-CH3; 4-CH3; 4-OCH3; 4-CHO; 3-OH,4-OCH3; 4-OH,3-OCH3; 2,5-(OCH3)2; 3,4-(OCH3)2; 3,4-(OCH2O); 3,4,5-(OCH3)3; 4-CHO.

OH

O N O H2N

O

N

R3 O

R2 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen3-yl)(aryl)methyl)pyrimidine-2,4(1H,3H)diones (4a-4t) 20 examples (yield: 80-98%)

Sulfamic acid (NH2SO3H; 30 mol%) EtOH : H2O (1:1 v/v; 3 mL)

1

R1

R3

OH

R1

N H2N

N

OH

6-Aminothiouracil (3', 0.25 mmol)

R2, R3 = H, H; CH3, H; CH3, CH3

OH

SH

N O

O H2N

N

SH

3-((4-Amino-6-hydroxy-2-mercaptopyrimidin -5-yl)(aryl)methyl)-4-hydroxy-2Hchromen-2-ones (4'a-4'f) 6 examples (yield: 66-97%)

Scheme 1. Ultrasound-assisted one-pot synthesis of diversely substituted 6-amino-5-((4-hydroxy-2-oxo-2Hchromen-3-yl)(aryl)methyl)pyrimidine-2,4(1H,3H)-diones (4/4′) under sulfamic acid catalysis in aqueous ethanol at ambient conditions

RESULTS AND DISCUSSION To determine the optimum reaction conditions, we carried out a series of trial reactions with 4hydroxycoumarin (1; 1 equiv), benzaldehyde (2a; 1 equiv) and 6-aminouracil (3a; 1 equiv) (Table 1, entries 1-15). We achieved the best result for our model reaction in preparing the desired product, 6amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(phenyl)methyl)pyrimidine-2,4(1H,3H)-dione (4a) in 3



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83% yield at 22 min (Table 1, entry 8), when we used 30 mol% of sulfamic acid as catalyst, aqueous ethanol (1:1; v/v) as solvent, and ultrasonication (130 W, 20 kHz) at 40% amplitude at ambient conditions. . Compound 4a was characterized by its physical and spectral (FT-IR, 1H NMR, and 13C NMR) studies. The overall results are summarized in Table 1. Table 1 Optimization of reaction conditions for the synthesis of substituted 6-amino-5-((4-hydroxy-2-oxo-2Hchromen-3-yl)(aryl)methyl)pyrimidine-2,4(1H,3H)-diones(4). OH +

O

OH NH

+

H2N

O

1

Entry

O

CHO

2a

N H

O

experimental conditions

O

NH O

O H2N

3a

N H

O

4a

Catalyst (mol%)

Solvent

Conditions

Time (min)

Yield(%)a,b



No catalyst

Neat

RT

10

NR



No catalyst

H2O

RT

10

NR



No catalyst

EtOH

RT

10

NR

4

No catalyst

H2O

Ultrasound 

90

34

4

No catalyst

EtOH

Ultrasound 

90

38

5

No catalyst

EtOH : H2O (1:1 v/v)

Ultrasound (60%)

90

45

6

Sulfamic acid (50 mol%)

H2O

Ultrasound (40%)

25

72

7



Ultrasound (40%)

22

84

8



Ultrasound (40%)

22

83

9



Ultrasound (40%)

24

69

10



Ultrasound (40%)

28

61

11



Ultrasound (30%)

30

73

12



Ultrasound (40%)

24

84

13



Ultrasound (40%)

25

74

14



Reflux

150

76

15



RT

360

73

16

L-Proline (30 mol%)


Reflux

210

74

17

L-Proline (30 mol%)


Ultrasound (40%)

60

66

aReactionconditions:

4-hydroxycoumarin (1; 0.25 mmol), benzaldehyde (2a; 0.25 mmol) and 6-aminouracil (3a; 0.25 mmol) in the presence or absence of catalyst(s) in neat/3 mL of water/ethanol/ethanol-waterat RT/reflux/ultrasound irradiation (US; 130 W, 20 kHz at 40-60% amplitude). bIsolated yields. RT: Room Temperature (28-30 C). NR: No reaction.

To explore the applicability of the present methodology, we then carried out a set of seven reactions between 4-hydroxycoumarin (1; 0.25 mmol), 3-bromobenzaldehyde (2b; 0.25 mmol)/44


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fluorobenzaldehyde

(2c;

trifluoromethylbenzaldehyde

0.25 (2e;

mmol)/4-cyanobenzaldehyde 0.25

(2d;

mmol)/4-formylbenzaldehyde

0.25

(2f;

0.25

mmol)/4mmol)/4-

methylbenzaldehyde (2g; 0.25 mmol)/4-methoxybenzaldehyde (2h; 0.25 mmol), and 6-aminouracil (3; 0.25 mmol) under the sulfamic acid-catalyzed optimized reaction conditions; all of them took place efficiently affording the desired products, viz. 6-amino-5-((4-bromophenyl) (4-hydroxy-2-oxo2H-chromen-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione (4b) (Table 2, entry 2)/ 6-amino-5-((4fluorophenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione (4c) (Table 2,

entry

3)/

6-amino-5-((4-cyanophenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)pyrimidine-

2,4(1H,3H)-dione (4c) (Table 2, entry 4)/ 6-amino-5-((4-trifluoromethylphenyl)(4-hydroxy-2-oxo-2Hchromen-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione

(4e)

(Table

2,

entry

5)

/6-amino-5-((4-

formylphenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione (4f) (Table 2, entry 6)/ 6-amino-5-((4-methyphenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)pyrimidine2,4(1H,3H)-dione (4g) (Table 2, entry 7) /6-amino-5-((4-methoxyphenyl)(4-hydroxy-2-oxo-2Hchromen-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione (4h) (Table 2, entry 8), in 86%, 95%, 93%, 91%, 92%, 98% and 97% yields, respectively, within 10-25 min. We then performed satisfactorily a set of two more reactions with di-substituted benzaldehydes such as 4-hydroxy-3-methoxybenzaldehyde and 3,4-methylenedioxybenzaldehyde using the identical reaction conditions to have the desired products, 6-amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(4-hydroxy-3-methoxyphenyl)methyl)pyrimidine2,4(1H,3H)-dione (4i) (Table 2, entry 9) and 6-amino-5-(benzo[d][1,3]dioxol-5-yl(4-hydroxy-2-oxo2H-chromen-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione (4j) (Table 2, entry 10), respectively in 87% and 93% yields at 12 and 30 min. To explore the credibility of the present method, we planned to verify the reaction by replacing 6aminouracil with its two different derivatives, viz. 6-amino-N-methyluracil and 6-amino-N,Ndimethyluracil. Accordingly, we performed two more sets of such reactions between 4hydroxycoumarin, substituted benzaldehydes and 6-amino-N-methyluracil (Table 2; entries 11-15)/6amino-N,N-dimethyluracil (Table 2, entries 16-20) under the optimized reactions conditions; to our delight all these reactions underwent smoothly leading to the formation of desired products such as 6amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(phenyl)methyl)-1-methylpyrimidine-2,4(1H,3H)diones (4k-4o) (Table 2; entries 11-15) and 6-amino-5-((4-hydroxy-2-oxo-2H-chromen-3yl)(phenyl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-diones (4p-4t) (Table 2; entries 16-20), respectively, with yields ranging from 81-98% and 80-97% at 12-30 min. The experimental observations are shown in Table 2.

5


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Table 2 Synthesis of diversely substituted 6-amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(aryl)methyl)pyrimidine-2,4(1H,3H)-dione (4) R1 O

CHO

OH

N +

O 1 (1 equiv)

Entry

R1

O

+

N R2

H2N

2 (1 equiv)

R3 O

OH Sulfamic acid (30 mol%) EtOH : H2O (1:1; v/v) Ultrasound irradiation (US)

N O

Substituent (R2)

Substituent (R3)

Product

1

H

H

H

2

3-Br

H

3

4-F

4

O H2N

N

R3 O

2

4 (4a  4t)

3 (1 equiv)

Substituent (R1)

O

E-factor (g/g)d

R

Time (min)

Yield (%)a,b

E-factor (g/g)c

TON

4a

20

83

0.28

0.37

3.0

272-275

Reported 

H

4b

10

86

0.21

0.29

3.0

265-267



H

H

4c

12

95

0.11

0.18

3.4

255-258



4-CN

H

H

4d

25

93

0.14

0.19

3.3

262-264



5

4-CF3

H

H

4e

15

91

0.16

0.23

3.3

263-266



6

4-CHO

H

H

4f

10

92

0.15

0.23

3.3

288-290



7

4-CH3

H

H

4g

15

98

0.07

0.15

3.6

245-247



8

4-OCH3

H

H

4h

20

98

0.07

0.14

3.6

235-238



9

4-OH, 3-OCH3

H

H

4i

12

87

0.21

0.28

3.1

217-220



10

3,4-(O-CH2-O)

H

H

4j

30

93

0.13

0.20

3.3

248-251



11

H

CH3

H

4k

20

98

0.07

0.15

3.6

210-212



12

3-CH3

CH3

H

4l

30

96

0.09

0.16

3.4

213-215



Melting point ( C) Found

6


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13

4-OCH3

CH3

H

4m

20

98

0.07

0.14

3.4

242-243



14

3,4-(OCH3)2

CH3

H

4n

22

81

0.30

0.37

2.9

243-245



15

3,4,5-(OCH3)3

CH3

H

4o

15

95

0.10

0.16

3.4

270-271



16

H

CH3

CH3

4p

12

94

0.13

0.20

3.3

228-230

188-19245

17

4-CH3

CH3

CH3

4q

21

97

0.08

0.15

3.4

216-218



18

3-OH, 4-OCH3

CH3

CH3

4r

18

91

0.15

0.21

3.3

188-191



19

4-OH, 3-OCH3

CH3

CH3

4s

15

97

0.08

0.15

3.4

208-210



20

3,4-(OCH3)2

CH3

CH3

4t

30

80

0.31

0.39

2.9

164-166



aReaction

Conditions: 4-hydroxycoumarin (1; 0.25 mmol), aromatic aldehydes (2; 0.25 mmol) and 6-aminouracils (3; 0.25 mmol) in 3 mL of aqueous ethanol (1:1 v/v) in the presence of sulfamic acid (30 mol%) as catalyst under ultrasound irradiation (130 W, 20 kHz at 40% amplitude) at ambient conditions; bIsolated yields; cE-factor calculated based on the reuse of the catalyst up to the 5th run; dE-factor calculated considering non-recovery of the catalyst after the 5th run; TON: turn over number

7



Page 8 of 33

Inspired by the experimental outcomes, we then planned to check the reaction with 6-amino2-thiouracil (4-amino-6-hydroxy-2-mercaptopyrimidine; 3′) as a substitute of 6-aminouracil (3); accordingly, a three-component tandem reaction between 4-hydrxycoumarin (1; 0.25 mmol), benzaldehyde (2a; 0.25 mmol) and 6-amino-2-thiouracil (3′; 0.25 mmol) was run using the identical reaction conditions. The reaction proceeded efficiently furnishing the expected product, 3-((4-amino6-hydroxy-2-mercaptopyrimidin-5-yl)(4-methoxyphenyl)methyl)-4-hydroxy-2H-chromen-2-one (4′a) in excellent yield of 96% at 22 min (Table 3, entry 1). We then carried out a set of five reactions with diverse aldehydes, and isolated the desired 3-((4-amino-6-hydroxy-2-mercaptopyrimidin-5yl)(aryl)methyl)-4-hydroxy-2H-chromen-2-ones (4′b-4′f) (Table 3, entries 2-6) with good yields (6697%) at 12-25 min. The results are indicated in Table 3. However, the reaction was found not to undergo with aliphatic aldehydes. We carried out four sets of reactions between 4-hydroxycoumarin, butyraldehyde/isobutyraldehyde and 6-aminouracil/6-amino-2-thiouracil using identical reaction conditions, but failed to isolate the desired products in all the cases. This is probably due to the relatively lower electron-deficiency of the carbonyl carbon in aliphatic aldehydes coupled with the possible tautomeric effect to be experienced by aliphatic aldehydes in acidic reaction media. Table 3 Synthesis of substituted 3-((4-amino-6-hydroxy-2-mercaptopyrimidin-5-yl)(aryl)methyl)-4-hydroxy2H-chromen-2-ones 4′ R1 OH +

O

R1

Substituent

H2N 2 (1 equiv)

Product

(R1)

OH

N

OH


N

+

O

1 (1 equiv)

Entry

OH

CHO

EtOH : H2O (1:1 v/v) Ultrasound irradiation (US)

SH

N O H2N

O

N

SH

4' (4'a - 4'f)

3' (1 equiv)

Time

Yield

(min)

(%)a,b

E-factor (g/g)c

E-factor (g/g)d

TON

Melting point ( C) Found

Reported

1

4-OCH3

4′a

22

96

0.14

0.21

3.4

213-215



2

4-CHO

4′f

12

88

0.24

0.31

3.1

288-291



3

3-OH, 4-OCH3

4′b

15

73

0.49

0.58

2.6

226-228



4

4-OH, 3-OCH3

4′c

12

66

0.63

0.73

2.4

247-249



5

2,5-(OCH3)2

4′d

20

97

0.12

0.18

3.4

201-203



6

3,4-(OCH3)2

4′e

25

84

0.29

0.37

3.0

199-201



aReaction

Conditions: 4-hydroxycoumarin (1; 0.25 mmol), aldehydes (2; 0.25 mmol) and 6-amino-2-thiouracil (3′; 0.25 mmol) in 3 mL of aqueous ethanol (1:1 v/v) in the presence of sulfamic acid (30 mol%) as catalyst under ultrasound irradiation (130 W, 20 kHz at 40% amplitude) at ambient conditions; bIsolated yields; ; cEfactor calculated based on the reuse of the catalyst up to the 5th run; dE-factor calculated considering nonrecovery of the catalyst after the 5th run; TON: turn over number

8


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All the products (4a–4t and 4′a–4′f) were isolated as pure upon filtration of the resulting reaction mixture after adding with 2 mL of distilled water. All the compounds, except 4p, are new and were fully characterized based on their analytical data and detailed spectral studies including FT-IR, 1H NMR, 13C NMR, and DEPT-135. Out of our observations upon monitoring the reaction sequence, we herein propose a possible mechanism (Scheme 2) for the ultrasound-promoted sulfamic acid-catalyzed one-pot synthesis of functionalized 6-amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(aryl)methyl)pyrimidine-2,4(1H,3H)dione (4) from three-component reaction of 4-hydroxycoumarin (1), aromatic aldehydes (2) and 6aminouracile (3) in aqueous ethanol. We assume that firstly the sulfamic acid-activated aldehyde (2) takes part in the Claisen-Schmidt type condensation with 6-aminouracil (3) to generate a chalcone intermediate 6 (could not be isolated) that is immediately attacked by the nucleophile, 4hydroxycoumarin (1) , through its C-3 to give adduct 7, which in turn tautomerizes to the desired product 4 and the catalyst (NH2SO3H) is released out for the next cycle Only one molecule of water is eliminated (as a green waste) in this transformation (Scheme 2).

NH3SO3

O

H O +

R1 2

H2N

EtOH-H2O (1:1), NH2SO3H ultrasound irradiation

NH

N H 3

Claisen-Schmidt condensation CC bond formation

O

NH

O H

HN

N H

O

 H2O

O3SH3N O

OH

NH O H2N 4

N H

O

(tautomerism)

N O H NH3SO3 Intermediate 6 O HN

H O

R1

O O

O H

1

NH

NH2SO3H

NH

(removal of water)

Adduct 5

R1

O

O3SH3N

R1 O

R1 O H

O

O H2N

N H

O

EtOH-H2O

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 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(nucleophilic attack through ring-C atom) (CC bond formation)

Adduct 7

Scheme 2: Proposed mechanism for the ultrasound-assisted sulfamic acid-catalyzed three-component one-pot synthesis of substituted 6-amino-5-((4-hydroxy-2-oxo-2H-chromen-3yl)(aryl)methyl)pyrimidine-2,4(1H,3H)-dione (4) at ambient conditions We checked the effectiveness of this ultrasound-assisted protocol for somewhat scaled-up (on the gram scale; 5 mmol scale) experiment with our model reaction (Table 2; entry 1); the large-scale reaction

afforded

the

target

product,

6-amino-5-((4-hydroxy-2-oxo-2H-chromen-3-

yl)(phenyl)methyl)pyrimidine-2,4(1H,3H)-dione (4a), in 87% yield within 9


32 min. It has been


Page 10 of 33

revealed that the large-scale reaction is almost similar with 0.25 mmol scale entry (Table 2, entry 1) in terms of respective yield but requires more time (32 min instead of 22 min) to complete. In addition, the reaction media containing the catalyst and residual solvent obtained upon filtration of the reaction mixture after the completion of the reaction was successfully reused up to the fifth run in the case of a representative entry (Table 2, entry 1), viz. reaction between 4-hydroxycoumarin, benzaldehyde, and 6-aminouracil. The desired product 4a was isolated in 83-81% yields, almost similar to that from the 1st run, but the time-frame was found to be elongated from 22 min (1st run) to 38 min (5th run), thereby indicating in the reduction of catalytic efficiency of the catalyst used in the 1st run over further uses. The results are graphically represented in Figure 2.

Reuse of reaction media for the model reaction (entry 1) 90 80 70 60 50 40 30 20 10 0 Time (min) %Yield

83

83

22

25

1st Run 22 83

2nd Run 25 83

82

30

3rd Run 30 82

Time (min)

82

81

35

38

4th Run 35 82

5th Run 38 81

%Yield

Figure 2. Reusability of reaction media for a representative entry (Table 2, entry 1) Based on the well-established working formulas76-84 we calculated diverse ranges of green metrics such as turnover number (TON), turnover frequency (TOF), E-factor, atom economy (AE), atom efficiency (AEf), carbon efficiency (CE), optimum efficiency (OE), effective mass yield (EMY), reaction mass efficiency (RME), mass productivity (MP), mass intensity (MI) and process mass intensity (PMI), and solvent and water intensity (SI and WI), for all the compounds (4a-4t and 4'a4'f) synthesized using this present protocol, considering both reusing of the catalyst for next runs and also its non-recovery after the 5th run (see Supporting Information). The calculated effective mass yield, atom economy and atom efficiency for the method amounts to up to 93.64%, 96.39% and 93.98%, respectively. The calculated carbon efficiency (80.0 to 96.0%) for this process is also quite good. As reaction mass efficiency (RME) includes all reactant mass, catalyst, yield, and atom economy, it is the most useful metric to determine the greenness of a process. Calculations of RME (61.34 to 93.64% and 57.94 to 97.72%, respectively upon reuse of the catalyst in the 1st run and nonrecovery after the 5th run) also indicate excellent green credential of the present method. Similarly, 10


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process mass intensity (PMI) evaluations (42.75 to 64.37 g/g and 41.33 to 64.47 g/g, respectively) also corroborate with this fact. The calculated E-factors (g/g) are found to be in the range of 0.63 to 0.07 and 0.73 to 0.14, respectively upon reuse of the catalyst in the 1st run and non-recovery after the 5th run, which are indicative of the considerable greenness of this present method. TON and TOF (min1) for all the products were found to be in the range of 2.4 to 3.6, and 0.30 to 0.10 min1, respectively. All other parameters have also been found to be in order. Respective data and their calculations for all the entries are documented in the Supporting Information.

CONCLUSION In conclusion, we accomplished an ultrasound-promoted expedient and facile alternative green synthetic protocol for a series of biologically promising substituted 6-amino-5-((4-hydroxy-2-oxo-2Hchromen-3-yl)(aryl)methyl)pyrimidine-2,4(1H,3H)-diones (4/4′) from the one-pot three-component reaction between 4-hydroxycoumarin (1), substituted aromatic aldehydes (2), and 6-aminouracils (3)/6-amino-2-thiouracil (3′) using sulfamic acid as an eco-friendly solid acid-catalyst in aqueous ethanol at ambient conditions. The key features of this present protocol are the use of commercially cheap starting materials and reagents, metal-free one-pot synthesis, good to excellent yields, short reaction times, energy efficiency, reusability of reaction media, avoidance of tedious column chromatography for product isolation/purification , large-scale synthetic applicability, high atomeconomy and TON, and low E-factor. All the worked-out green metrics are found to be highly satisfactory, thereby supporting substantial green credentials of the process. Evaluation of biological profiles of this new series of molecular hybrids is now under study in our laboratory.

EXPERIMENTAL SECTION General Considerations A Shimadzu (FT-IR 8400S) FT-IR spectrophotometer was used to record infrared spectra with KBr disc. 1H and 13C NMR spectra were collected at 400 MHz and 100 MHz, respectively, on a Bruker DRX spectrometer using DMSO-d6 and CDCl3 as solvent. An ultrasound probe-sonicator (Sonics; Model: VCX 130; 20 kHz, 130 W) was used for sonication. 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

6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-

yl)(aryl)methyl)pyrimidine-2,4(1H,3H)-diones (4/4′) A mixture of 4-hydroxycoumarin (1; 0.25 mmol), aromatic aldehydes (2; 0.25 mmol), 6-aminouracils (3; 0.25 mmol)/6-amino-2-thiouracil (3′), sulfamic acid (30 mol%; 0.007 g) and aqueous ethanol (1:1 11



v/v; 3 mL) added sequentially in an oven-dried glass-vessel was irradiated with ultrasound (130 W, 20 kHz at 40% amplitude) for stipulated time-frame (12-30 min as monitored by TLC). Upon completion of the reaction, the resulting reaction mixture was diluted with 2 mL of distilled water when a solid mass precipitated out, which was filtered off affording the desired products 4/4′ in pure form. Each of the synthesized compounds was fully characterized based on its analytical as well as spectral studies including FT-IR, 1H-NMR, 13C-NMR and DEPT-135.

Spectral and Analytical Data of All the Synthesized Compounds (4/4′). 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(phenyl)methyl)pyrimidine-2,4(1H,3H)-dione (4a) White amorphous powder; yield: 83% (0.078 g, 0.25 mmol scale); mp = 272-275 C, Rf (60% ethyl acetate/petrol ether) 0.20. IR (KBr) max: 3455 (OH), 3369 (NH2), 3183 (NH), 3025, 2904, 1745 (lactone CO), 1661 (CONH), 1625, 1598, 1569, 1548, 1451, 1379, 1187, 1048, 932, 757, 608, 545, 434 cm1; 1H NMR (400 MHz, DMSO-d6):  = 14.05 (br s, 1H, -OH), 11.09 (d, 1H, J = 0.8 Hz, -NH), 10.78 (d, 1H, J = 0.4 Hz, -NH), 7.81 (dd, 1H, J = 8.0, 1.6 and 1.2 Hz, Ar-H), 7.64 (dt, 1H, J = 8.4, 7.2, 1.6 and 0.8 Hz, Ar-H), 7.42 (d, 1H, J = 7.6 Hz, Ar-H), 7.35 (dt, 1H, J = 7.6, 7.2 and 0.8 Hz, ArH), 7.27-7.24 (m, 2H, Ar-H), 7.22-7.12 (m, 3H, Ar-H), 6.62 (br s, 2H, -NH2), 5.51 (s, 1H, -CH) ppm; 13C

NMR (100 MHz, DMSO-d6):  = 167.40 (CO), 165.83 (CONH), 163.85 (CONH), 155.89, 152.39,

149.65, 138.78, 132.72, 128.53 (2C), 126.80 (2C), 126.17, 124.64, 124.09, 117.58, 116.53, 105.54, 86.47, 35.01 (-CH) ppm. Elemental analysis: calcd (%) for C20H15N3O5: C, 63.66; H, 4.01; N, 11.14. Found: C, 63.56; H, 4.00; N, 11.11. 6-Amino-5-((3-bromophenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)pyrimidine-2,4(1H,3H)dione (4b) White amorphous powder; yield: 86% (0.098 g, 0.25 mmol scale); mp = 265-267 C; Rf (60% ethyl acetate/petrol ether) 0.25. IR (KBr)max: 3344 (OH), 3200-3120 (NH2 and NH), 3061, 1712 (lactone CO), 1659 (CONH), 1629, 1574, 1456, 1389, 1162, 1047, 904, 846, 762, 679, 543, 439 cm1; 1H

NMR (400 MHz, DMSO-d6):  = 14.04 (br s, 1H, -OH); 11.12 (d, 1H,J = 0.4 Hz, -NH), 10.79 (s,

1H, -NH), 7.82 (dd, 1H,J = 8.0 and 1.6 Hz, Ar-H), 7.67-7.62 (m, 1H, Ar-H), 7.42 (d, 1H, J = 8.4 Hz, Ar-H), 7.38-7.34 (m, 1H, Ar-H), 7.29-7.27 (m, 1H, Ar-H), 7.24-7.21 (m, 1H, Ar-H), 7.19-7.13 (m, 2H, Ar-H), 6.66 (s, 2H, -NH2),5.53 (s, 1H, -CH) ppm;

13C

NMR (100 MHz, DMSO-d6):  =

167.42(CO), 165.65(CONH), 163.93(CONH), 156.04, 152.59, 150.16, 149.65, 142.12, 132.85, 130.71, 129.60, 129.23, 126.21, 124.71, 124.17, 117.60, 116.61, 105.39, 85.96, 34.95(-CH) ppm. Elemental analysis: calcd (%) for C20H14BrN3O5: C, 52.65; H, 3.09; N, 9.21. Found: C, 52.60; H, 3.10; N, 9.18. 12


Page 12 of 33

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6-Amino-5-((4-fluorophenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione (4c) White amorphous powder; yield: 95% (0.094 g, 0.25 mmol scale); mp = 255-258 C; Rf (60% ethyl acetate/petrol ether) 0.20. IR (KBr) max: 3404 (OH), 3360 (NH2), 3158 (NH), 3047, 1712 (lactone CO), 1659 (CONH), 1630, 1600, 1574, 1504, 1449, 1387, 1224, 1157, 1047, 1020, 957, 837, 766, 631, 547, 441 cm1; 1H NMR (400 MHz, DMSO-d6):  = 14.05 (br s, 1H, -OH), 11.09 (s, 1H, NH), 10.78 (s, 1H, -NH), 7.83-7.80 (m, 1H, Ar-H), 7.64 (dt, 1H, J = 8.0, 7.6 and 1.2 Hz, Ar-H), 7.42 (d, 1H, J = 8.4 Hz, Ar-H), 7.35 (t, 1H, J = 7.6 Hz, Ar-H), 7.29-7.22 (m, 1H, Ar-H), 7.18-7.14 (m, 1H, Ar-H), 7.06 (d, 1H, J = 8.8 Hz, Ar-H), 7.03-6.95 (m, 1H, Ar-H), 6.64 (s, 2H, -NH2), 5.48 (s, 1H,-CH) ppm; 13C NMR (100 MHz, DMSO-d6):  = 167.43 (CO), 165.80 (CONH), 163.89 (CONH), 155.93, 152.45, 149.68, 132.79 (2C), 128.85, 128.78, 124.68, 124.51, 124.14, 116.57, 115.27, 115.06, 105.70, 104.07, 86.42, 34.55 (-CH) ppm. Elemental analysis: calcd (%) for C20H14FN3O5: C, 60.76; H, 3.57; N, 10.63. Found: C, 60.68; H, 3.55; N, 10.60. 4-((6-Amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)(4-hydroxy-2-oxo-2H-chromen-3yl)methyl)benzonitrile (4d) White amorphous powder; yield: 93% (0.093 g, 0.25 mmol scale); mp = 262-264 C; Rf (60% ethyl acetate/petrol ether) 0.14. IR (KBr) max: 3341 (OH), 3236 (NH2), 3165 (NH), 2226 (CN), 1728 (lactone CO), 1660 (CONH), 1620, 1573, 1449, 1383, 1244, 1156, 1016, 956, 884, 763, 626, 547, 449 cm1; 1H NMR (400 MHz, DMSO-d6):  = 14.03 (br s, 1H, -OH), 11.14 (s, 1H, -NH), 10.82 (s, 1H, NH), 7.82-7.78 (m, 1H, Ar-H), 7.71 (d, 1H, J = 8.4 Hz, Ar-H), 7.67-7.61 (m, 2H, Ar-H), 7.43 (d, 1H, J = 8.0 Hz, Ar-H), 7.39 (d, 2H, J = 7.6 Hz, Ar-H), 7.27-7.21 (m, 1H, Ar-H), 6.69 (s, 2H, -NH2), 5.58 (s, 1H,-CH) ppm;

13C

NMR (100 MHz, DMSO-d6):  = 167.46 (CO), 165.62 (CONH), 163.99

(CONH), 156.11, 152.54, 150.17, 149.65, 145.54, 132.91, 132.47, 128.22 (2C), 124.72, 124.20, 119.49, 117.57, 116.61, 109.07, 105.17, 85.81, 35.56 (-CH) ppm. Elemental analysis: calcd (%) for C21H14N4O5: C, 62.69; H, 3.51; N, 13.92. Found: C, 62.63; H, 3.50; N, 13.88. 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(4-(trifluoromethyl)phenyl)methyl)

pyrimidine-

2,4(1H,3H)-dione (4e) White amorphous powder; yield: 91% (0.101 g, 0.25 mmol scale); mp = 263-266 C; Rf (60% ethyl acetate/petrol ether) 0.20. IR (KBr) max: 3401 (OH), 3341 (NH2), 3167 (NH), 3069, 1712 (lactone CO), 1659 (CONH), 1624, 1451, 1328, 1118, 1069, 902, 849, 765, 618, 582, 538, 437 cm1; 1H

NMR (400 MHz, DMSO-d6):  = 14.05 (br s, 1H, -OH), 11.14 (s, 1H, -NH), 10.83 (s, 1H, -NH),

7.83-7.79 (m, 1H, Ar-H), 7.68-7.63 (m, 1H, Ar-H), 7.60 (d, 1H, J = 8.4 Hz, Ar-H), 7.56-7.49 (m, 1H, 13



Ar-H), 7.43 (d, 1H, J = 8.0 Hz, Ar-H), 7.39-7.34 (m, 2H, Ar-H), 7.31-7.21 (m, 1H, Ar-H), 6.69 (br s, 2H, -NH2), 5.59 (s, 1H, -CH) ppm;

13C

NMR (100 MHz, DMSO-d6):  = 167.42 (CO), 165.61

(CONH), 163.94 (CONH), 156.03, 152.46, 149.62, 144.22, 132.85, 127.82 (2C), 125.40, 124.68, 124.55 (-CF3), 124.16, 123.47, 117.55, 116.56, 116.01, 105.30, 85.95, 35.24 (-CH) ppm. Elemental analysis: calcd (%) for C21H14F3N3O5: C, 56.64; H, 3.17; N, 9.44. Found: C, 56.61; H, 3.15; N, 9.41. 4-((6-Amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)(4-hydroxy-2-oxo-2H-chromen-3yl)methyl)benzaldehyde (4f) White amorphous powder; yield: 92% (0.093 g, 0.25 mmol scale); mp = 288-290 C; Rf (60% ethyl acetate/petrol ether) 0.14. IR (KBr) max: 3387 (OH), 3180 (NH2), 3162 (NH), 3041, 2967, 1715 (lactone CO), 1681 (CHO), 1660 (CONH), 1620, 1573, 1450, 1383, 1213, 1167, 1049, 903, 837, 762, 679, 538, 463 cm1;1H NMR (400 MHz, DMSO-d6):  = 14.04 (br s, 1H, -OH), 11.14 (s, 1H, -NH), 10.82 (s, 1H, -NH), 9.94 (s, 1H, -CHO), 7.83-7.78 (m, 3H, Ar-H), 7.67-7.63 (m, 1H,Ar-H), 7.43 (d, 1H,J = 8.4 Hz, Ar-H), 7.38 (t, 2H, J = 8.4 and 8.0Hz, Ar-H), 7.34-7.28 (m, 1H, Ar-H), 6.68 (s, 2H, NH2), 5.59 (s, 1H,-CH) ppm;13C NMR (100 MHz, DMSO-d6):  = 193.06 (-CHO), 167.48 (CO), 165.68 (CONH), 164.00 (CONH), 156.03, 152.51, 149.68, 146.72, 134.76, 132.89, 129.92, 127.80 (2C), 124.73, 124.20, 123.49, 117.60, 116.61, 105.42, 86.14, 35.63 (-CH) ppm. Elemental analysis: calcd (%) for C21H15N3O6: C, 62.22; H, 3.73; N, 10.37. Found: C, 62.18; H, 3.74; N, 10.39. 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(p-tolyl)methyl)pyrimidine-2,4(1H,3H)-dione (4g) White amorphous powder; yield: 98% (0.096 g, 0.25 mmol scale); mp = 245-247 C; Rf (60% ethyl acetate/petrol ether) 0.25. IR (KBr) max: 3381 (OH and NH2), 3148 (NH), 3042, 2968, 2916, 1713 (lactone CO), 1629 (CONH), 1519, 1449, 1380, 1246, 1160, 1020, 955, 827, 763, 678, 639, 540, 445 cm1; 1H NMR (400 MHz, DMSO-d6):  = 14.05 (br s, 1H, -OH), 11.06 (s, 1H, -NH), 10.76 (s, 1H, -NH), 7.80 (dd, 1H, J = 8.0 and 1.2 Hz, Ar-H), 7.66-7.61 (m, 1H, Ar-H), 7.42 (d, 1H, J = 8.4 Hz, Ar-H), 7.35 (t, 1H, J = 7.2 Hz, Ar-H), 7.05-6.98 (m, 4H, Ar-H), 6.59 (s, 2H, -NH2), 5.45 (s, 1H,-CH), 2.24 (s, 3H, -CH3) ppm; 13C NMR (100 MHz, DMSO-d6):  = 167.37 (CO), 165.85 (CONH), 163.81 (CONH), 155.82, 152.37, 150.18, 149.65, 135.62, 135.05, 132.69, 129.12, 128.67, 126.71, 124.65, 124.06, 117.58, 116.52, 105.68, 86.58, 34.67 (-CH), 20.90 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.48; H, 4.36; N, 10.79. 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(4-methoxyphenyl)methyl)pyrimidine-2,4(1H,3H)dione (4h) Light yellow amorphous powder; yield: 98% (0.100 g, 0.25 mmol scale); mp = 235-238 C; Rf (60% ethyl acetate/petrol ether) 0.24. IR (KBr) max: 3398 (OH), 3360 (NH2), 3184 (NH), 3003, 14


Page 14 of 33

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2901, 2834, 1717 (lactone CO), 1636 (CONH), 1600, 1510, 1448, 1247, 1184, 1043, 954, 899, 678, 541, 440 cm1; 1H NMR (400 MHz, DMSO-d6):  = 14.04 (br s, 1H, -OH), 11.07 (s, 1H, -NH), 10.76 (s, 1H, -NH), 7.81 (dd, 1H, J= 7.6, 1.2 and 0.8 Hz, Ar-H), 7.63 (dt, 1H, J = 8.0, 7.6, 1.6 Hz, Ar-H), 7.42 (d, 1H, J = 8.0 Hz, Ar-H), 7.35 (t, 1H, J = 8.0 and 7.2 Hz, Ar-H), 7.03 (d, 1H, J = 8.4 Hz, Ar-H), 6.95 (d, 1H, J = 8.4 Hz, Ar-H), 6.79 (d, 1H, J =8.8 Hz, Ar-H), 6.75 (d, 1H, J = 8.8 Hz, Ar-H), 6.60 (s, 2H, -NH2), 5.44 (s, 1H,-CH), 3.69 (s, 3H, Ar-OCH3) ppm;

13C


167.41 (CO), 165.86 (CONH), 163.84 (CONH), 157.84, 155.83, 152.41, 150.22, 149.70, 132.71, 130.41, 127.91, 124.67, 124.10, 117.64, 116.56, 113.95, 113.52, 105.88, 86.71, 55.42 (Ar-OCH3), 34.34 (-CH) ppm. Elemental analysis: calcd (%) for C21H17N3O6: C, 61.91; H, 4.21; N, 10.31.Found: C, 61.84; H, 4.19; N, 10.33. 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(4-hydroxy-3-methoxyphenyl)methyl)

pyrimidine-

2,4(1H,3H)-dione (4i) Light yellow amorphous powder; yield: 87% (0.092 g, 0.25 mmol scale); mp = 217-220 C; Rf (60% ethyl acetate/petrol ether) 0.28. IR (KBr) max: 3443 (Ar-OH), 3407 (OH), 3200 (NH2), 3163 (NH), 2960, 2900, 1725 (lactone CO), 1662 (CONH), 1619, 1600, 1574, 1517, 1451, 1384, 1357, 1269, 1204, 1136, 1031, 950, 899, 815, 795, 764, 628, 579, 435 cm1; 1H NMR (400 MHz, DMSOd6):  = 13.99 (br s, 1H, Ar-OH), 12.52 (br s, 1H, -OH), 11.04 (s, 1H, -NH), 10.72 (s, 1H, -NH), 7.837.80 (m, 1H, Ar-H), 7.63 (t, 1H, J = 8.0 and 7.6 Hz, Ar-H), 7.41 (d, 1H, J = 8.0 Hz, Ar-H), 7.37-7.32 (m, 2H, Ar-H), 6.65-6.63 (m, 2H, Ar-H), 6.57 (br s, 2H, -NH2), 5.42 (br s, 1H, -CH), 3.59 (s, 3H, ArOCH3) ppm; 13C NMR (100 MHz, DMSO-d6):  = 167.44 (CO), 166.10 (CONH), 163.86 (CONH), 153.98, 152.39, 149.69, 147.78, 145.23, 133.19, 132.67, 124.68, 124.40, 123.66, 119.33, 116.84, 116.56, 115.66, 111.81, 86.89, 56.26 (Ar-OCH3), 34.56 (-CH) ppm. Elemental analysis: calcd (%) for C21H17N3O7: C, 59.57; H, 4.05; N, 9.93. Found: C, 59.53; H, 4.02; N, 9.90. 6-Amino-5-(benzo[d][1,3]dioxol-5-yl(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)

pyrimidine-

2,4(1H,3H)-dione (4j) Light yellow amorphous powder; yield: 93% (0.098 g, 0.25 mmol scale); mp = 248-251 C; Rf (60% ethyl acetate/petrol ether) 0.40. IR (KBr) max: 3456 (OH), 3341 (NH2), 3181 (NH), 3018, 2880, 1723 (lactone CO), 1667 (CONH), 1630, 1574, 1491, 1481, 1389, 1241, 1038, 930, 818, 760, 679, 568, 438 cm1; 1H NMR (400 MHz, DMSO-d6):  = 14.05 (br s, 1H, -OH), 11.06 (s, 1H, -NH), 10.74 (s, 1H, -NH), 7.81 (d, 1H, J = 7.6 Hz, Ar-H), 7.63 (t, 1H, J = 7.6 Hz, Ar-H), 7.41 (d, 1H, J = 8.0 Hz, Ar-H), 7.35 (t, 1H, J = 7.6 Hz, Ar-H), 6.76 (d, 1H, J = 8.0 Hz, Ar-H), 6.73-6.69 (m, 2H, Ar-H), 6.59-6.58 (brs, 2H, -NH2), 5.95 (s, 2H, -O-CH2-O-), 5.42 (s, 1H, -CH) ppm;

13C

NMR (100 MHz,

DMSO-d6):  = 167.40 (CO), 165.79 (CONH), 163.84 (CONH), 155.86, 152.43, 150.21, 149.69, 15



Page 16 of 33

147.82, 145.74, 132.71, 124.65, 124.11, 119.67, 117.65, 116.56, 108.18, 107.69, 105.86, 101.22 (-OCH2-O-), 86.71, 34.82 (-CH) ppm. Elemental analysis: calcd (%) for C21H15N3O7: C, 59.86; H, 3.59; N, 9.97. Found: C, 59.81; H, 3.57; N, 9.94. 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(phenyl)methyl)-1-methylpyrimidine-2,4(1H,3H)dione (4k) White amorphous powder; yield: 98% (0.096 g, 0.25 mmol scale); mp = 210-212 C; Rf (60% ethyl acetate/petrol ether) 0.64. IR (KBr) max: 3388 (OH), 3329 (NH2), 3191 (NH), 3021, 2949, 2903, 2802, 2362, 1698 (lactone CO), 1670 (CONH), 1616, 1573, 1498, 1452, 1364, 1253, 1217, 1155, 1109, 1047, 906, 762, 617, 540, 416 cm1; 1H NMR (400 MHz, DMSO-d6):  = 14.47 (brs, 1H, -OH), 11.32(s, 1H, -NH), 7.83 (dd, 1H, J = 8.0, 1.6 and 1.2 Hz, Ar-H), 7.67-7.63 (m, 1H, Ar-H), 7.44 (d, 1H, J = 8.4 Hz, Ar-H), 7.38-7.34 (m, 2H, -NH2), 7.26-7.20 (m, 2H, Ar-H), 7.18-7.14 (m, 3H, Ar-H), 7.08 (d, 1H,J = 7.2 Hz, Ar-H), 5.57 (s, 1H, -CH), 3.32 (s, 3H, -NCH3) ppm;

13C

NMR (100 MHz,

DMSO-d6):  = 166.34 (CO), 165.35 (CONCH3), 164.48 (CONH), 157.16, 152.45, 150.59, 150.07, 140.13, 132.83, 128.53, 127.01, 126.84, 126.16, 124.76, 124.19, 117.65, 116.61, 105.13, 87.45, 36.06 (-CH), 29.96 (-NCH3) ppm. Elemental analysis: calcd (%) for C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.40; H, 4.36; N, 10.70. 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(m-tolyl)methyl)-1-methylpyrimidine-2,4(1H,3H)dione (4l) White amorphous powder; yield: 96% (0.097 g, 0.25 mmol scale); mp = 213-215 C; Rf (60% ethyl acetate/petrol ether) 0.50. IR (KBr) max: 3428 (OH), 3340-3294 (NH2), 3211 (NH), 3040, 2890, 1700 (lactone CO), 1629 (CONH), 1571, 1500, 1353, 1242, 1106, 1050, 949, 805, 760, 682, 571, 439 cm1; 1H NMR (400 MHz, DMSO-d6):  = 14.45 (br s, 1H, -OH), 11.31 (s, 1H, -NH), 7.83 (dd, 1H, J = 7.6, 1.6 and 1.2 Hz, Ar-H), 7.67-7.63 (m, 1H, Ar-H), 7.43 (d, 1H, J = 7.6 Hz, Ar-H), 7.38-7.34 (m, 1H, Ar-H), 7.33 (br s, 2H, -NH2), 7.12 (t, 1H, J = 8.0 and 7.6 Hz, Ar-H), 6.96 (d, 2H, J = 5.2 Hz, ArH), 6.93 (d, 1H, J = 8.0 Hz, Ar-H), 5.53 (s, 1H, -CH), 3.31 (s, 3H, -NCH3),2.21 (s, 3H, Ar-CH3) ppm; 13C NMR (100 MHz, DMSO-d6):  = 165.87 (CO), 164.87 (CONH), 163.99 (CONCH3), 156.63, 151.94, 149.60, 138.37, 136.97, 132.32, 127.93, 126.85, 126.42, 124.28, 123.72, 123.46, 117.17, 116.12, 104.71, 87.06, 35.47 (-CH), 29.46 (-NCH3), 21.20 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C22H19N3O5: C, 65.18; H, 4.72; N, 10.37. Found: C, 65.14; H, 4.70; N, 10.40. 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(4-methoxyphenyl)methyl)-1-methylpyrimidine2,4(1H,3H)-dione (4m)

16


Page 17 of 33 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 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


White amorphous powder; yield: 98% (0.103 g, 0.25 mmol scale); mp = 242-243 C; Rf (60% ethyl acetate/petrol ether) 0.30. IR (KBr) max: 3401 (OH), 3360 (NH2), 3209 (NH), 2810 (OCH3), 1728 (lactone CO), 1637 (CONH), 1612, 1572, 1518, 1511, 1379, 1248, 1175, 1045, 901, 846, 753, 679, 566, 434 cm1; 1H NMR (400 MHz, DMSO-d6):  = 14.45 (br s, 1H, -OH), 11.30 (s, 1H, -NH), 7.82 (dd, 1H, J = 8.0 and 1.2 Hz, Ar-H), 7.66-7.62 (m, 1H, Ar-H), 7.43 (d, 1H, J = 8.0 Hz, Ar-H), 7.37 (d, 1H, J = 7.6 Hz, Ar-H), 7.34 (br s, 2H,-NH2), 7.04 (d, 2H, J = 8.4 Hz, Ar-H), 6.79 (d, 2H, J = 8.8 Hz, Ar-H), 5.51 (s, 1H, -CH), 3.69 (s, 3H, -OCH3), 3.31 (s, 3H, -NCH3) ppm;

13C

NMR (100

MHz, DMSO-d6):  = 165.84 (CO), 164.83 (CONH), 163.95 (CONCH3), 157.33, 156.57, 151.93, 149.59, 132.29, 129.99, 127.43 (2C), 124.24, 123.66, 117.18, 116.11, 113.42 (2C), 104.94, 87.14, 54.94 (Ar-OCH3), 34.87 (-CH), 29.45 (-NCH3) ppm. Elemental analysis: calcd (%) for C22H19N3O6: C, 62.70; H, 4.54; N, 9.97. Found: C, 62.63; H, 4.52; N, 9.92. 6-Amino-5-((3,4-dimethoxyphenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)-1-methylpyrimidine2,4(1H,3H)-dione (4n) White amorphous powder; yield: 81% (0.091 g, 0.25 mmol scale); mp = 243-245 C. Rf (60% ethyl acetate/petrol ether) 0.15. IR (KBr) max: 3398(OH), 3360 (NH2), 3209 (NH), 2932, 1724 (lactone CO), 1642 (CONH), 1615, 1569, 1514, 1453, 1375, 1249, 1135, 1025, 957, 813, 707, 679, 573, 449 cm1; 1H NMR (400 MHz, DMSO-d6):  = 14.42 (br s, 1H, -OH), 11.29 (s, 1H, -NH), 7.83 (dd, 1H, J = 8.0 and 1.2 Hz, Ar-H), 7.66-7.62 (m, 1H, Ar-H), 7.43 (d, 1H, J = 8.0 Hz, Ar-H), 7.37 (d, 1H, J = 8.0 Hz, Ar-H), 7.33 (d, 2H, J = 4.8Hz, -NH2), 6.80 (d, 1H, J = 8.4 Hz, Ar-H), 6.71 (d, 1H, J = 1.2 Hz, Ar-H), 6.65 (d, 1H, J = 8.4 Hz, Ar-H), 5.52 (s, 1H, -CH), 3.69 (s, 3H, Ar-OCH3), 3.59 (s, 3H, Ar-OCH3), 3.31 (s, 3H, -NCH3) ppm;

13C

NMR (100 MHz, DMSO-d6):  = 165.83 (CO), 164.88

(CONH), 164.02 (CONCH3), 156.57, 151.92, 149.60, 148.46, 147.09, 132.29, 130.64, 124.27, 123.63, 118.52, 117.17, 116.12, 111.54, 111.06, 104.92, 87.21, 55.63 (Ar-OCH3), 55.44 (Ar-OCH3), 35.12 (CH), 29.46 (-NCH3) ppm. Elemental analysis: calcd (%) for C23H21N3O7: C, 61.19; H, 4.69; N, 9.31. Found: C, 61.11; H, 4.68; N, 9.28. 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(3,4,5-trimethoxyphenyl)methyl)-1-methylpyrimidine2,4(1H,3H)-dione (4o) White amorphous powder; yield: 95% (0.114 g, 0.25 mmol scale); mp = 270-271 C; Rf (60% ethyl acetate/petrol ether) 0.30. IR (KBr) max: 3422 (OH), 3345 (NH2), 3250-3190 (NH), 2966, 2937, 2831, 1718 (lactone CO), 1659 (CONH), 1619, 1504, 1449, 1232, 1128, 1043, 995, 955, 805, 757, 639, 564, 490, 434 cm1; 1H NMR (400 MHz, DMSO-d6):  = 14.44 (s, 1H, -OH), 11.30 (s, 1H, -NH), 7.85 (dd, 1H, J= 7.6 and 1.2 Hz, Ar-H), 7.66-7.62 (m, 1H, Ar-H), 7.43 (d, 1H, J = 8.4 Hz, Ar-H), 7.37 (d, 1H,J = 7.6 Hz, Ar-H), 7.34 (d, 2H, J = 3.6Hz, Ar-H), 6.43 (s, 2H, -NH2), 5.53 (s, 1H, -CH), 3.62 17



(s, 3H, Ar-OCH3), 3.60 (s, 6H, 2 × Ar-OCH3), 3.31 (s, 3H, -NCH3) ppm;

Page 18 of 33

13C

NMR (100 MHz,

DMSO-d6):  = 166.30 (CO), 165.42 (CONH), 164.60, 157.08, 153.03 (2C), 152.42, 150.10, 136.36, 134.65, 132.80, 124.79, 124.12, 117.63, 116.62, 105.26, 104.79 (2C), 87.64, 60.44 (Ar-OCH3), 56.41 (2×Ar-OCH3), 36.14 (-CH), 29.96 (-NCH3) ppm. Elemental analysis: calcd (%) for C24H23N3O8: C, 59.87; H, 4.82; N, 8.73. Found: C, 59.81; H, 4.80; N, 8.71. 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(phenyl)methyl)-1,3-dimethyl-

pyrimidine-

2,4(1H,3H)-dione (4p)45 White amorphous powder; yield: 94% (0.095 g, 0.25 mmol scale); mp = 228-230 C; Rf (60% ethyl acetate/petrol ether) 0.56. IR (KBr) max: 3465 (OH), 3367 (NH2), 3200 (NH), 3045, 2951, 1705 (lactone CO), 1660 (CONH), 1621, 1572, 1494, 1444, 1355, 1330, 1252, 1204, 1196, 1148, 1060, 1041, 956, 916, 865, 757, 618, 550, 509, 430, 409 cm1; 1H NMR (400 MHz, CDCl3):  = 13.43 (s, 1H, -OH), 7.99 (d, 1H, J = 7.2 Hz, Ar-H), 7.59-7.55 (m, 1H, Ar-H), 7.35-7.32 (m, 2H, Ar-H), 7.317.27 (m, 2H, Ar-H), 7.23-7.18 (m, 3H, Ar-H), 6.45 (s, 2H, -NH2), 5.75 (s, 1H, -CH), 3.57 (s, 3H, NCH3), 3.33 (s, 3H, -NCH3) ppm; 13C NMR (100 MHz, CDCl3):  = 168.06 (CO), 165.13 (CONCH3), 164.70 (CONCH3), 154.55, 152.40, 150.63, 137.43, 132.27, 128.42 (2C), 126.29 (2C), 124.54, 124.32, 117.41, 116.24 (2C), 104.18, 89.55, 36.58 (-CH), 29.83 (-NCH3), 28.37(-NCH3) ppm. Elemental analysis: calcd (%) for C22H19N3O5: C, 65.18; H, 4.72; N, 10.37. Found: C, 65.12; H, 4.70; N, 10.39. 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(p-tolyl)methyl)-1,3-dimethyl-

pyrimidine-

2,4(1H,3H)-dione (4q) White amorphous powder; yield: 97% (0.102 g, 0.25 mmol scale); mp = 216-218 C; Rf (60% ethyl acetate/petrol ether) 0.35. IR (KBr) max: 3457 (OH), 3214 (NH2), 2951, 1703 (lactone CO), 1649 (CONCH3), 1571, 1493, 1486, 1443, 1354, 1252, 1196, 1065, 956, 912, 849, 767, 621, 577, 543, 487, 432 cm1; 1H NMR (400 MHz, CDCl3):  = 13.47 (s, 1H, -OH), 7.99 (d, 1H, J = 7.6 Hz, Ar-H), 7.59-7.55 (m, 1H, Ar-H), 7.32 (t, 2H, J = 8.4 and 8.0 Hz, Ar-H), 7.10-7.06 (m, 4H, Ar-H), 6.51 (s, 2H, -NH2), 5.71 (s, 1H, -CH), 3.57 (s, 3H, -NCH3), 3.33 (s, 3H, -NCH3), 2.31 (s, 3H, Ar-CH3) ppm; 13C

NMR (100 MHz, CDCl3):  = 168.08 (CO), 165.16 (CONCH3), 164.68 (CONCH3), 154.61,

152.37, 150.66, 135.78, 134.30, 132.24, 129.18 (2C), 126.16 (2C), 124.55, 124.31, 117.45, 116.21, 104.36, 89.53, 36.26 (-CH), 29.88 (-NCH3), 28.72 (-NCH3), 20.98 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C23H21N3O5: C, 65.86; H, 5.05; N, 10.02. Found: C, 65.80; H, 5.04; N, 10.06. 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(3-hydroxy-4-methoxyphenyl)methyl)-1,3dimethylpyrimidine-2,4(1H,3H)-dione (4r) 18


Page 19 of 33 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 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


White amorphous powder; yield: 91% (0.103 g, 0.25mmol scale); mp = 188-191 C; Rf (60% ethyl acetate/petrol ether) 0.70. IR (KBr) max: 3448 (OH), 3198 (NH2), 2954, 2781, 1693 (lactone CO), 1667 (CONCH3), 1620, 1573, 1510, 1444, 1358, 1271, 1127, 1066, 957, 872, 764, 676, 636, 501, 434 cm1; 1H NMR (400 MHz, CDCl3):  = 13.49 (s, 1H, -OH), 7.98 (d, 1H, J = 7.6 Hz, Ar-H), 7.58-7.54 (m, 1H, Ar-H), 7.34-7.29 (m, 2H, Ar-H), 6.74 (d, 2H, J = 8.4 Hz, Ar-H), 6.67-6.64 (m, 1H, Ar-H),6.43 (s, 2H,-NH2), 5.66 (s, 1H, -CH), 3.84 (s, 3H, Ar-OCH3), 3.55 (s, 3H, -NCH3), 3.33(s, 3H, NCH3) ppm; 13C NMR (100 MHz, CDCl3):  = 168.12 (CO), 165.25 (CONCH3), 164.79 (CONCH3), 154.61, 152,48, 150.73, 145.66, 145.10, 132.36, 130.79, 124.66, 124.39, 117.85, 117.53, 116.33, 112.93, 110.53, 104.32, 89.76, 55.99 (Ar-OCH3), 36.12 (-CH), 29.93 (-NCH3), 28.84 (-NCH3) ppm. Elemental analysis: calcd (%) for C23H21N3O7: C, 61.19; H, 4.69; N, 9.31. Found: C, 61.12; H, 4.67; N, 9.28. 6-Amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(4-hydroxy-3-methoxyphenyl)methyl)-1,3dimethylpyrimidine-2,4(1H,3H)-dione (4s) White amorphous powder; yield: 97% (0.109 g, 0.25 mmol scale); mp = 208-210 C; Rf (60% ethyl acetate/petrol ether) 0.40. IR (KBr) max: 3526 (OH), 3491 (-OH), 3231 (NH2), 3002, 2961, 2935, 1696 (lactone CO), 1646 (CONCH3), 1610, 1570, 1505, 1448, 1354, 1262, 1108, 1066, 1047, 957, 885, 766, 697, 637, 582, 460, 434 cm1; 1H NMR (400 MHz, DMSO-d6):  = 13.95 (br s, 1H, OH), 7.86 (dd, 1H, J = 8.0, 1.6, 1.2 Hz, Ar-H), 7.68-7.63 (m 1H, Ar-H), 7.44 (d, 1H, J = 8.0 Hz, ArH), 7.37 (dt, 1H, J = 7.6, 7.2, 1.2, 0.8 Hz, Ar-H), 7.29 (br s, 2H, -NH2), 6.66 (d, 1H, J = 6.8 Hz, ArH), 6.63 (s, 1H, Ar-H), 6.54 (dd, 1H, J = 8.4, 1.2, 0.8 Hz, Ar-H), 5.56 (s, 1H, -CH), 3.60 (s, 3H, OCH3), 3.38 (s, 3H, -NCH3), 3.16 (s, 3H, -NCH3) ppm; 13C NMR (100 MHz, DMSO-d6):  = 166.29 (CO), 164.56 (CONCH3), 164.27 (CONCH3), 155.45, 152.38, 150.56, 147.84, 145.22, 132.84, 129.23, 124.80, 124.13, 119.26, 117.41, 116.60, 115.63, 111.90, 105.46, 87.66, 56.32 (Ar-OCH3), 36.00 (CH), 30.99 (-NCH3), 28.65 (-NCH3) ppm. Elemental analysis: calcd (%) for C23H21N3O7: C, 61.19; H, 4.69; N, 9.31. Found: C, 61.13; H, 4.68; N, 9.27. 6-Amino-5-((3,4-dimethoxyphenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)-1,3dimethylpyrimidine-2,4(1H,3H)-dione (4t) White amorphous powder; yield: 80% (0.093 g, 0.25 mmol scale); mp = 164-166 C; Rf (60% ethyl acetate/petrol ether) 0.45. IR (KBr) max: 3408 (OH), 3371 (-OH), 3228 (NH2), 3001, 2951, 2840, 1709 (lactone CO), 1665 (CONCH3), 1613, 1568, 1510, 1444, 1334, 1258, 1243, 1144, 1026, 956, 811, 760, 636, 500, 449 cm1; 1H NMR (400 MHz, CDCl3):  = 13.45 (s, 1H, -OH), 7.98 (d, 1H, J = 7.6 Hz, Ar-H), 7.59-7.55 (m, 1H, Ar-H), 7.35-7.30 (m, 2H, Ar-H), 6.78 (d, 1H, J = 8.4 Hz, Ar-H), 6.72 (d, 1H, J = 8.8 Hz, Ar-H), 6.68 (br s, 1H, Ar-H), 6.48 (s, 2H, -NH2), 5.71 (s, 1H, -CH), 3.84 (s, 19



3H, Ar-OCH3), 3.73 (s, 3H, Ar-OCH3), 3.57 (s, 3H, -NCH3), 3.33 (s, 3H, -NCH3) ppm; 13C NMR (100 MHz, CDCl3):  = 168.02 (CO), 165.18 (CONCH3), 164.66 (CONCH3), 154.51, 152.36, 150.66, 148.89, 147.56, 132.31, 129.82, 124.46, 124.37, 118.56, 117.35, 116.24, 111.01, 110.27, 104.39, 89.60, 56.06 (Ar-OCH3), 55.79 (Ar-OCH3), 36.12 (-CH), 29.87(-NCH3), 28.70 (-NCH3) ppm. Elemental analysis: calcd (%) for C24H23N3O7: C, 61.93; H, 4.98; N, 9.03. Found: C, 61.88; H, 4.96; N, 9.00. 3-((4-Amino-6-hydroxy-2-mercaptopyrimidin-5-yl)(4-methoxyphenyl)methyl)-4-hydroxy-2Hchromen-2-one (4′a) White amorphous powder; yield: 96% (0.101 g, 0.25 mmol scale); mp = 213-215 C; Rf (60% ethyl acetate/petrol ether) 0.30. IR (KBr) max: 3500 (OH), 3396 (OH), 3199 (NH2), 3128, 3128, 2971, 2905, 2839, 2591 (SH), 2359, 1668 (lactone CO), 1617, 1570, 1510, 1440, 1360, 1327, 1246, 1216, 1180, 1033, 954, 834, 759, 677, 595, 544, 513 cm1. 1H NMR (400 MHz, DMSO-d6):  = 13.48 (br s, 1H, -OH), 12.49 (s, 1H, Ar-OH), 12.16 (s, 1H, -SH), 7.81(dd, 1H, J= 8.0, 1.6 and 1.2 Hz, Ar-H), 7.667.62 (m, 1H, Ar-H), 7.42 (d, 1H, J = 8.0 Hz, Ar-H), 7.35 (dt, 1H,J = 7.6, 7.2, 0.8 and 0.4 Hz,Ar-H), 7.03 (d, 2H,J = 8.4 Hz, Ar-H), 6.80 (d, 2H, J = 8.8 Hz, AR-H), 6.73 (br s, 2H, -NH2), 5.49 (s, 1H, CH), 3.69 (s, 3H, Ar-OCH3) ppm;

13C

NMR (100 MHz, DMSO-d6):  = 172.75 (CAr-OH), 165.18

(CAr-SH), 164.51 (CAr-NH2), 163.20 (CO), 157.51, 154.32, 151.97, 132.35, 129.27, 127.53 (2C), 124.25, 123.64, 117.08, 116.12, 113.57(2C), 105.18, 90.99, 54.99 (Ar-OCH3), 33.99 (-CH) ppm. Elemental analysis: calcd (%) for C21H17N3O5S: C, 59.57; H, 4.05; N, 9.92. Found: C, 59.50; H, 4.03; N, 9.95. 4-((4-Amino-6-hydroxy-2-mercaptopyrimidin-5-yl)(4-hydroxy-2-oxo-2H-chromen-3yl)methyl)benzaldehyde (4′b) White amorphous powder; yield: 88% (0.093 g, 0.25 mmol scale); mp = 288-291 C; Rf (60% ethyl acetate/petrol ether) 0.53. IR (KBr) max: 3432 (OH), 3340 (OH), 3206 (NH2), 3080, 2920, 2880, 2583 (SH), 2361, 1660 (lactone CO), 1619, 1548, 1431, 1344, 1214, 1177, 1130, 1043, 947, 901, 838, 759, 668, 598, 543, 435 cm1; 1H NMR (400 MHz, DMSO-d6):  = 13.49 (br s, 1H, -OH), 12.56 (s, 1H, Ar-OH), 12.22 (s, 1H, -SH), 9.96 (s, 1H, -CHO),7.83-7.79 (m, 3H, Ar-H), 7.68-7.64 (m, 1H, ArH), 7.45-7.42 (m, 2H, Ar-H), 7.40-7.35 (m, 2H, Ar-H), 6.83 (br s, 2H, -NH2), 5.67 (s, 1H, -CH) ppm; 13C

NMR (100 MHz, DMSO-d6):  = 193.09 (CHO), 173.33 (CAr-OH), 165.44 (CAr-SH), 165.04 (CAr-

NH2), 163.82 (CO), 154.93, 152.52, 146.00, 134.86, 132.96, 129.97 (2C), 127.86 (2C), 124.74, 124.20, 117.51, 116.61, 105.23, 90.78, 35.68 (-CH) ppm. Elemental analysis: calcd (%) for C21H15N3O5S: C, 59.85; H, 3.59; N, 9.97. Found: C, 59.82; H, 3.61; N, 9.93.

20


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3-((4-Amino-6-hydroxy-2-mercaptopyrimidin-5-yl)(3-hydroxy-4-methoxyphenyl)methyl)-4-hydroxy2H-chromen-2-one (4′c) White amorphous powder; yield: 73% (0.080 g, 0.25 mmol scale); mp = 226-228 C; Rf (60% ethyl acetate/petrol ether) 0.50. IR (KBr) max: 3490 (OH), 3403 (OH), 3198 (NH2), 3055, 2960, 2898, 2830 (OCH3), 2551 (SH), 2360, 1667 (lactone CO), 1618, 1556, 1515, 1447, 1273, 1241, 1211, 1175, 1124, 1041, 1021, 867, 816, 759, 671, 605, 551 cm1; 1H NMR (400 MHz, DMSO-d6):  = 13.52 (br s, 1H, -OH), 12.49 (s, 1H, Ar-OH), 12.16 (br s, 1H, -SH), 8.78 (s, 1H, Ar-OH), 7.83 (dd, 1H, J = 7.6, 1.6 and 1.2 Hz, Ar-H), 7.67-7.63 (m, 1H, Ar-H), 7.43 (d, 1H, J = 8.0 Hz, Ar-H), 7.37 (dt,1H,J = 7.6, 1.2 and 0.8 Hz, Ar-H), 6.78 (d, 1H, J = 8.4 Hz, Ar-H), 6.71 (br s, 2H,-NH2), 6.58 (d, 1H, J = 1.2 Hz, Ar-H), 6.52-6.48 (m, 1H, Ar-H), 5.46 (s, 1H, -CH), 3.71 (s, 3H, Ar-OCH3) ppm; 13C NMR (100 MHz, DMSO-d6):  = 173.20 (CAr-OH), 165.62 (CAr-SH), 164.92 (CAr-NH2), 163.69 (CO), 154.69, 152.39, 146.79, 146.33, 132.81, 130.49, 124.71, 124.13, 117.54, 117.35, 116.56, 114.34, 112.69, 105.44, 91.52, 56.11 (Ar-OCH3), 34.47 (-CH) ppm. Elemental analysis: calcd (%) for C21H17N3O6S: C, 57.40; H, 3.90; N, 9.56. Found: C, 57.35; H, 3.89; N, 9.58. 3-((4-Amino-6-hydroxy-2-mercaptopyrimidin-5-yl)(4-hydroxy-3-methoxyphenyl)

methyl)-4-hydroxy-

2H-chromen-2-one (4′d) Pale yellow powder; yield: 66% (0.073 g, 0.25 mmol scale); mp = 247-249 C; Rf (60% ethyl acetate/petrol ether) 0.20. IR (KBr) max: 3425 (OH), 3320 (OH), 3200 (NH2), 3160, 2966, 2898, 2840, 2551 (SH), 2360, 2336, 1700 (lactone CO), 1636, 1550, 1510, 1434, 1369, 1321, 1242, 1212, 1172, 1034, 933, 903, 753, 676, 607, 544, 497 cm1; 1H NMR (400 MHz, DMSO-d6):  = 13.41 (br s, 1H, -OH), 12.45 (br s, 1H, Ar-OH), 12.12 (br s, 1H, -SH), 8.75 (br s, 1H, Ar-OH), 7.85-7.81 (m, 1H, Ar-H), 7.68-7.62 (m, 1H, Ar-H), 7.44 (d, 1H, J = 8.0 Hz, Ar-H), 7.39-7.37 (m, 2H,-NH2), 6.70-6.67 (m, 3H, Ar-H), 6.56-6.52 (m, 1H, Ar-H), 5.51 (br s, 1H, -CH), 3.63 (s, 3H, Ar-OCH3) ppm;13C NMR (100 MHz, DMSO-d6):  = 173.17 (CAr-OH), 166.10 (CAr-SH), 164.96 (CAr-NH2), 163.66 (CAr-CO), 152.40, 145.39, 133.19, 132.75, 128.64, 124.70, 124.05, 123.67, 119.40, 117.53, 116.56, 115.71, 111.89, 105.77, 91.60,56.33 (Ar-OCH3), 34.66 (-CH) ppm. Elemental analysis: calcd (%) for C21H17N3O6S: C, 57.40; H, 3.90; N, 9.56. Found: C, 57.33; H, 3.88; N, 9.59. 3-((4-Amino-6-hydroxy-2-mercaptopyrimidin-5-yl)(2,5-dimethoxyphenyl)methyl)-4-hydroxy-2Hchromen-2-one (4′e) White amorphous powder; yield: 97% (0.110 g. 0.25 mmol scale); mp = 201-203 C; Rf (60% ethyl acetate/petrol ether) 0.70. IR (KBr) max: 3460 (OH), 3394 (OH), 3200 (NH2), 3072, 3061, 3048, 2990, 2958, 2897, 2832, 2734, 2519 (SH), 1662 (lactone CO), 1629, 1555, 1497, 1458, 1433, 1313, 1228, 1173, 1050, 906, 865, 752, 601, 540, 436 cm1; 1H NMR (400 MHz, DMSO-d6):  = 13.21 (br 21



s, 1H, -OH), 12.44 (s, 1H, Ar-OH), 12.08 (s, 1H, -SH), 7.79 (dd, 1H, J = 7.6, 1.6 and 1.2 Hz, Ar-H), 7.62-7.58 (m, 1H, Ar-H), 7.38 (d, 1H, J = 8.0 Hz, Ar-H), 7.33 (dt, 1H, J= 7.6, 7.2, 1.2 and 0.8 Ar-H), 6.82 (d, 1H,J = 8.8Hz,Ar-H), 6.78-6.73 (m, 1H, Ar-H), 6.66 (d, 1H, J = 2.4 Hz, Ar-H), 6.63 (br s, 2H, -NH2), 5.49 (s, 1H, -CH), 3.63 (s, 3H, Ar-OCH3), 3.50 (s, 3H, Ar-OCH3) ppm; 13C NMR (100 MHz, DMSO-d6):  = 172.46 (CAr-OH), 164.44 (CAr-SH), 162.59 (CAr-NH2), 162.10 (CO), 153.66, 152.71, 151.68, 151.41, 131.99, 127.93, 124.11, 123.47, 117.07, 115.95, 115.62, 111.97, 110.51, 105.75, 90.49, 56.10 (CAr-OCH3), 55.18 (CAr-OCH3), 31.63 (-CH) ppm. Elemental analysis: calcd (%) for C22H19N3O6S: C, 58.27; H, 4.22; N, 9.27. Found: C, 58.24; H, 4.21; N, 9.30. 3-((4-Amino-6-hydroxy-2-mercaptopyrimidin-5-yl)(3,4-dimethoxyphenyl)methyl)-4-hydroxy-2Hchromen-2-one (4′f) White amorphous powder; yield: 84% (0.095 g, 0.25 mmol scale); mp = 199-201 C; Rf (60% ethyl acetate/petrol ether) 0.42. IR (KBr) max: 3446(OH), 3357(OH), 3286 (NH2), 3075, 2956, 2837, 2520 (SH), 2365, 1650 (lactone CO), 1620, 1553, 1516, 1457, 1318, 1243, 1147, 1054, 1027, 923, 812, 604, 538, 492 cm1; 1H NMR (400 MHz, DMSO-d6):  = 13.42 (br s, 1H, -OH), 12.47 (s, 1H, Ar-OH), 12.15 (s, 1H, -SH), 7.82 (dd, 1H, J = 7.6, 1.6 and 1.2 Hz, Ar-H), 7.66-7.62 (m, 1H, Ar-H), 7.42 (d, 1H, J = 8.0 Hz, Ar-H), 7.35 (dt, 1H, J = 7.6 and 0.8 Hz, Ar-H), 6.82 (d, 1H,J = 8.4 Hz, ArH), 6.72 (br s, 2H, -NH2), 6.69 (d, 1H, J = 1.6 Hz, Ar-H), 6.64 (d, 1H, J = 8.4 Hz, Ar-H), 5.51 (s, 1H, -CH), 3.70 (s, 3H, Ar-OCH3), 3.58 (s, 3H, Ar-OCH3) ppm;

13C


172.71 (CAr-OH), 165.13 (CAr-SH), 164.50 (CAr-NH2), 163.21 (CO), 154.27, 151.93, 148.50, 147.25, 132.30, 129.89, 124.23, 123.57, 118.61, 117.03, 116.09, 111.60, 111.02, 105.19, 90.98, 55.65 (CArOCH3), 55.44 (CAr-OCH3), 34.24 (-CH) ppm. Elemental analysis: calcd (%) for C22H19N3O6S: C, 58.27; H, 4.22; N, 9.27. Found: C, 58.23; H, 4.20; N, 9.29. ASSOCIATED CONTENT Supporting Information Scanned copies of respective 1H NMR and 13C NMR spectra for all the synthesized compounds (4a-4t and 4′a-4′f) along with working formulas for calculations of green metrics and respective calculated data for all the synthesized compounds (PDF) ACKNOWLEDGEMENTS This paper is dedicated to Professor David W. Allen, Sheffield Hallam University, UK, in honor of his dedicated contributions to the field of organic chemistry. Financial support (Grant No. EMR/2014/001220) from the Science and Engineering Research Board (SERB), Department of Science & Technology (DST), Government of India, New Delhi is gratefully acknowledged. IK and KN are thankful, respectively to the UGC and CSIR, New Delhi for awarding them Senior Research 22


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Fellowships. The authors are also thankful to DST-FIST Programme, and Department of Chemistry, Visva-Bharati University for infrastructural facilities. Notes The authors declare no competing financial interest. REFERENCES (1)

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_________

GRAPHICAL ABSTRACT 31



Ultrasound as an efficient green tool: An ultrasound-assisted expedient and green synthetic protocol for

functionalized

6-amino-5-((4-hydroxy-2-oxo-2H-chromen-3-yl)(aryl)methyl)pyrimidine-

2,4(1H,3H)-diones has been accomplished under and sulfamic acid-catalysis at ambient conditions.

______________________________________________________________________ Sustainable aspects and highlights        

Synthesis of a series of biologically interesting molecular hybrids via a newly developed advanced synthetic protocol Use of aqueous ethanol as the green solvent Use of sulfamic acid as a low-cost and eco-friendly solid acid-catalyst, thus a metal-free onepot synthesis No tedious column chromatography was required for purification of synthesized compounds; simple filtration warrants a practical method. Application of US as a green tool to expedite the reaction rate just at ambient conditions (room temperature and pressure) The protocol can be used for large scale synthesis (gram scale) Practically no waste (water is a green waste) and the filtrate can be reused for the next cycle Excellent green chemistry credentials with high atom-economy, low-E-factor, and high turnover number ___________

32


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Graphical abstract Figure 152x99mm (300 x 300 DPI)


Ultrasound-Promoted Expedient and Green ... - ACS Publications

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