Ultrasound-Assisted Expedient and Green Synthesis of a New Series

Subscriber access provided by Miami University Libraries

Article

Ultrasound-Assisted Expedient and Green Synthesis of a New Series of Diversely Functionalized 7-Aryl/heteroarylchromeno[4,3d]pyrido[1,2-a]pyrimidin-6(7H)-ones via One-Pot Multicomponent Reaction under Sulfamic Acid Catalysis at Ambient Conditions Goutam Brahmachari, Indrajit Karmakar, and Khondekar Nurjamal ACS Sustainable Chem. Eng., Just Accepted Manuscript • Publication Date (Web): 25 Jun 2018 Downloaded from http://pubs.acs.org on June 25, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 34 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

ACS Sustainable Chemistry & Engineering

Research Article (sc-2018-02448q.R2) Ultrasound-Assisted Expedient and Green Synthesis of a New Series of Diversely

Functionalized

7-Aryl/heteroarylchromeno[4,3-d]pyrido[1,2-

a]pyrimidin-6(7H)-ones via One-Pot Multicomponent Reaction under Sulfamic Acid Catalysis at Ambient Conditions Goutam Brahmachari*,a, Indrajit Karmakara and Khondekar Nurjamala a

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] *Corresponding author: Prof. Dr. Goutam Brahmachari (http://orcid.org/0000-0001-9925-6281)

________________________________________________________________ ABSTRACT: An ultrasound-assisted highly efficient, simple, and straightforward protocol for one-pot

synthesis of a new series of pharmaceutically relevant and diversely functionalized 7aryl/heteroarylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-ones (4) has been developed based on a three-component tandem reaction between 4-hydroxycoumarin (1), substituted aromatic aldehydes (2), and 2-aminopyridines (3) in the presence of sulfamic acid as a lowcost and eco-friendly solid acid-catalyst in aqueous ethanol at ambient conditions. Expedient metal-free synthesis, good to excellent yields, energy-efficiency, use of aqueous ethanol as reaction medium, easy isolation of products, no need of column chromatographic purification, high atom-economy and low E-factor, high turnover number (TON), ecofriendliness, and operational simplicity are some of the salient features of this newly developed protocol. KEYWORDS: Ultrasound, Sulfamic acid, One-pot multicomponent reaction, Green synthesis, Functionalized chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-ones

________________________________________________________________ INTRODUCTION Polyfunctionalized heterocyclic moieties, in particular, are found to occur abundantly within the frameworks of bioactive natural and synthetic lead molecules, drug candidates either marketed or under clinical trials, agrochemicals, cosmetics and dyes, and many other 1

ACS Paragon Plus Environment

ACS Sustainable Chemistry & Engineering 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

Page 2 of 34

application-oriented materials.1-4 Hence, research on the design and syntheses of new series of polyfunctionalized heterocycles is a topic of potential interest. Among O-heterocycles, natural coumarins and their synthetic analogs are widely known for their diverse array of significant pharmacological and biological properties.5-7 This privileged structural motif remains at the core of many useful antibiotics, such as novobiocin, coumermycin A1 and chlorobiocin,8 and serves as a valuable source of lead compounds for the design and development of effective antimicrobial and antifungal therapy drugs.9 The prospective role of coumarin derivatives as potential therapeutic candidates in the field of antioxidant,10 anticoagulant,11

anticancer,12-15

antituberculosis,16

anti-inflammatory,17

18

immunodeficiency virus ( HIV) and anti-Alzheimer’s drugs

19

anti-human

has also been documented in

the recent literatures.20,21 Similarly, pyrimidines are an important class of N-heterocycles, very much well-known for their potential applications both in the field of chemistry and biology.22,23 As part of our ongoing endeavors in designing and developing green protocols for biologically relevant heterocycles,24-39 we undertook a dedicated endeavor to construct a new polyfunctionalized heterocyclic architecture bearing both these two privileged scaffolds in combination with a view to impose somewhat extended biological and material properties, by designing an efficient and eco-friendly protocol! Accordingly, we have now been successful in developing an ultrasound-assisted facile and expedient method for the synthesis of a new series of diversely substituted 7-aryl/heteroaryl-chromeno[4,3-d]pyrido[1,2-a]pyrimidin6(7H)-ones (4) from a one-pot three-component reaction between 4-hydroxycoumarin (1), substituted aromatic aldehydes (2) and 2-aminopyridines (3) using sulfamic acid as an ecofriendly solid acid-catalyst in aqueous ethanol (1:1) at ambient conditions (28-30 C) (Scheme 1). The key advantages of this newly developed protocol are use of commercially available low-cost starting materials and nontoxic catalyst, metal-free synthesis, aqueous ethanol as reaction media, energy-efficiency, short reaction times, no column chromatography, good to excellent yields, low E-factor, high atom-economy, and high turnover number (TON). Ultrasound irradiation is, now-a-days, regarded as a very useful tool in enhancing the reaction rates, and is widely used in chemical transformations as it is associated with a number of benefits such as safety, energy savings, waste prevention, the use of ambient conditions, and the improvement in the mass transfer and product selectivity.40-44 The use of aqueous ethanol as safe and green solvent,45-48 metal-free synthesis,49-51 good use of green tools like ultrasonication,52,53 and optimum exploitations of the goodness of one-pot multicomponent reaction (MCR) strategy,54-58 molecular hybridization (MH) technique59,60 and ambient reaction conditions61-63 are, thus, the steps forward to the cause of green and sustainable chemistry.

2


Page 3 of 34 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


Scheme 1. Ultrasound-assisted one-pot synthesis of a new series of diversely substituted 7aryl/heteroaryl-chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-ones (4) under sulfamic acid catalysis at ambient conditions

RESULTS AND DISCUSSION From relevant literature survey coupled with our own experiences in designating heterocyclic compounds, we envisioned that such a chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one moiety might be designed out of a one-pot multicomponent reaction of its starting constituents such as 4-hydroxycoumarin, aldehyde, and 2-aminopyridine under some suitable reaction conditions. Accordingly, we primarily carried out a series of trial reactions of 4hydroxycoumarin (1-1; 1.0 equiv), 4-nitrobenzaldehyde (2-1; 1.0 equiv) and 2-aminopyridine (3-1; 1.0 equiv) under varying reaction conditions (Table 1). The best result (Table 1, entry 5) was observed when 20 mol% of sulfamic acid was used as catalyst in aqueous ethanol (1: 1; v/v) under ultrasound irradiation (130 W, 20 kHz at 40% amplitude) at ambient conditions to furnish the desired product, 7-(4-nitrophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)one (4-1) in a 96% yield just at 22 min; the isolate was characterized by its elemental and spectral (FT-IR, 1H-NMR and

13

C-NMR) studies. The overall results are documented in

Table 1.

3



Page 4 of 34

Table 1 Optimization of Reaction Conditions for the Synthesis of Substituted 7-Aryl/heteroarylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-ones (4)

entry 1 2 3 4 5 6 7 8 9 10 11

catalyst (mol%) no catalyst no catalyst no catalyst sulfamic acid (10 mol%) sulfamic acid (20 mol%) sulfamic acid (30 mol%) sulfamic acid (20 mol%) CH3COOH (30 mol%) L-proline (20 mol%) sulfamic acid (20 mol%) sulfamic acid (20 mol%)

solvent EtOH-H2O (1:1) EtOH-H2O (2:1) EtOH-H2O (1:2) EtOH-H2O (1:1) EtOH-H2O (1:1) EtOH-H2O (1:1) H2O EtOH-H2O (1:1) EtOH-H2O (1:1) EtOH-H2O (1:2) EtOH-H2O (1:1)

conditions ultrasound ultrasound ultrasound ultrasound ultrasound ultrasound ultrasound ultrasound ultrasound ultrasound reflux

12

sulfamic acid (20 mol%)

EtOH-H2O (1:1)

rt

time (min) 35 50 35 60 22 23 30 25 25 30 180 720

yield (%)a,b 60 42 57 77 96 95 70 57 70 72 80 82

a

Reaction conditions: 4-hydroxycoumarin (0.25 mmol), 4-nitrobenzaldehyde (0.25 mmol), and 2-aminopyridine (0.25 mmol), in 3 mL of water/water-ethanol in the presence or absence of catalyst under ultrasound irradiation (US; 130 W, 20 kHz at 40% amplitude)/ reflux (80 C)/room temperature (rt; 28-30 C). bIsolated yields.

Under the optimized experimental conditions, we then performed a set of five reactions between 4-hydroxycoumarin (1-1; 0.25 mmol), benzaldehyde (2-2; 0.25 mmol)/2fluorobenzaldehyde

(2-3;

0.25

mmol)/3-chlorobenzaldehyde

(2-4;

0.25

mmol)/4-

fluorobenzaldehyde (2-5; 0.25 mmol)/4-bromobenzaldehyde (2-6; 0.25 mmol), and 2aminopyridine (3-1; 0.25 mmol); all the reactions took place smoothly producing the desired products, viz. 7-phenylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-2) (Table 2, entry 2), 7-(2-fluorophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-3) (Table 2, entry 3), 7-(3-chlorophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-4) (Table 2, entry 4), 7-(4-fluorophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (45) (Table 2, entry 5), 7-(4-bromophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-6) (Table 2, entry 6) in 91, 96, 93, 92 and 91% yield, respectively, within 8–11 min. To explore the credibility of the present method, the combination of 4-hydroxycoumarin and 2aminopyridine was reacted with diverse aromatic aldehydes bearing the functionalities such 4


Page 5 of 34 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


as cyano, methyl, trifluoromethyl, N,N-dimethylamino, dichloro, mono- and dihydroxyl, mono- and dimethoxyls, methylenedioxyl and hydroxy-methoxyl using identical reaction conditions. All the reactions took place satisfactorily and generated the corresponding 7substituted chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-ones (4-7−4-18) (Table 2, entries 7−18) in good to excellent yields ranging from 70 to 97% under ultrasound assistance at ambient conditions within 8−32 min. It is evident from the variation of product-yields (47−4-18) that the presence of an electron-withdrawing group in the reacting aldehyde facilitates the reaction as expected; a somewhat relatively lower yield of 70% for 4-13 was isolated in case of 4-(N,N-dimethylamino)benzaldehyde (with an electron-releasing function) at comparatively longer time of 32 min. To our delight, 2-furylaldehyde (2-19) also took part in the reaction yielding 92% of the desired product, 7-(furan-2-yl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-19) within 8 min. With these fruitful experimental outcomes, we then checked whether the present protocol is eligible to generate bis(chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)one)

scaffold

upon

reaction

with

bis-carboxyaldehyde

such

as

phthalaldehyde,

isophthalaldehyde, and terephthalaldehyde. Hence, we carried out the reaction between 4hydroxycoumarin (2.0 equiv), 2-aminopyridine (2.0 equiv) and bis-carboxyaldehyde (1.0 equiv) in aqueous ethanol containing 20 mol% of sulfamic acid as catalyst under ultrasound irradiation at ambient conditions; both phthalaldehyde and isophthalaldehyde were found not to take part in the reaction (possibly due to steric crowding), while terephthalaldehyde gave only the chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one scaffold [viz. 4-(6-oxo-6,7dihydrochromeno[4,3-d]pyrido[1,2-a]pyrimidin-7-yl)benzaldehyde 4-20; 96% yield within 15 min] keeping the second carboxyaldehyde (CHO) function intact. This is a very interesting observation, indeed, and the present protocol thus offers a way to synthesize functionalized chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one scaffolds having a carboxyaldehyde group within the framework. Encouraged by these results, we carried out our model reaction just replacing 2aminopyridine with 4-methyl-2-aminopyridine under the identical reaction conditions in the presence of 20 mol% sulfamic acid as catalyst, and obtained the desired product, 11-methyl7-(4-nitrophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-21), with 95% yield at 7 min. A set of seven such reactions with varying aromatic aldehydes with electrondonating and –withdrawing substituents were then performed under the identical reaction conditions; all the reactions (Table 2; entries 22-28) took place efficiently affording 5



Page 6 of 34

substituted chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-ones (4-22 - 4-28) in 74-95% yields within 4-35 min. Herein also 4-(N,N-dimethylamino)benzaldehyde required relatively a longer time of 35 min to complete the reaction (Table 2; entry 23). 2-Furylaldehyde and terephthalaldehyde were also found to furnish the desired products,

7-(furan-2-yl)-11-

methylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-29; 81% yield at 6 min) and 4(11-methyl-6-oxo-6,7-dihydrochromeno[4,3-d]pyrido[1,2-a]pyrimidin-7-yl)benzaldehyde (430; 91% yield at 4.5 min), respectively. The overall results are summarized in Table 2. All the products (4-1 - 4-30) were isolated as pure upon filtration of the resulting reaction mixture added with 2 mL of distilled water. All of them are new and were fully characterized based on their analytical data and detailed spectral studies including FTIR, 1H NMR, NMR, and DEPT-135.

6


13

C

Page 7 of 34 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


Table 2 Synthesis of Diversely Substituted 7-Aryl/heteroarylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-ones (4)

Entry

Substituent (R1)

Substituent (R2)

Product

Time (min)

Yield (%)a,b

E-factor (g/g)c

E-factor (g/g)d

TON

Melting point ( C) Found

Reported

1

4-NO2C6H4

H

4-1

22

94

0.18

0.24

4.8

225-226



2

C6H5

H

4-2

9

91

0.24

0.31

4.6

211-212



3

2-FC6H4

H

4-3

8

96

0.17

0.23

4.8

112-113



4

3-ClC6H4

H

4-4

11

93

0.19

0.25

4.6

177-178



5

4-FC6H4

H

4-5

10

92

0.22

0.28

4.6

224-225



6

4-BrC6H4

H

4-6

10

91

0.21

0.26

4.6

240-242



7

4-OHC6H4

H

4-7

10

91

0.23

0.29

4.6

157-158



8

3,4-(OH)C6H3

H

4-8

18

92

0.20

0.27

4.6

180-181



9

2,4-Cl2C6H3

H

4-9

32

95

0.16

0.21

4.8

136-138



10

4-OCH3C6H4

H

4-10

15

92

0.22

0.28

4.6

206-207



11

3-CH3C6H4

H

4-11

17

91

0.22

0.28

4.6

137-138



12

4-CH3C6H4

H

4-12

12

90

0.23

0.30

4.6

229-230



7


ACS Sustainable Chemistry & Engineering 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

Page 8 of 34

13

4-N(CH3)2C6H4

H

4-13

32

70

0.57

0.65

3.6

182-183



14

3-OH,4-OCH3C6H3

H

4-14

25

93

0.20

0.26

4.6

189-190



15

3,4-(OCH3)2C6H3

H

4-15

25

93

0.19

0.24

4.6

215-216



16

3,4-(OCH2O)C6H3

H

4-16

24

92

0.21

0.27

4.6

218-219



17

4-CNC6H4

H

4-17

8

97

0.15

0.21

4.8

228-229



18

4-CF3C6H4

H

4-18

10

94

0.17

0.23

4.8

235-236



19

2-Furyl

H

4-19

8

92

0.22

0.29

4.6

175-176



20

4-CHOC6H4

H

4-20

15

96

0.16

0.22

4.8

215-216



21

4-NO2C6H4

CH3

4-21

7

95

0.16

0.22

4.8

240-241



22

4-OCH3C6H4

CH3

4-22

17

89

0.24

0.30

4.4

213-214



23

3,4-(OCH2O)C6H3

CH3

4-23

25

74

0.39

0.46

3.8

127-128



24

4-N(CH3)2C6H4

CH3

4-24

35

84

0.31

0.38

4.2

196-197



25

2-FC6H4

CH3

4-25

4

83

0.34

0.41

4.2

127-128



26

4-FC6H4

CH3

4-26

7

95

0.16

0.22

4.8

236-237



27

4-CF3C6H4

CH3

4-27

4

93

0.18

0.23

4.6

250-251



28

4-CNC6H4

CH3

4-28

8

70

0.58

0.66

3.6

218-219



29

2-Furyl

CH3

4-29

6

81

0.37

0.45

4.0

188-189



30

4-CHOC6H4

CH3

4-30

4.5

91

0.23

0.29

4.6

220-221



a

Reaction conditions: 4-hydroxycoumarin (1; 0.25 mmol), aromatic aldehydes (2; 0.25 mmol), and 2-aminopyridines (3; 0.25 mmol) in 3 mL of aqueous ethanol (1:1 v/v) in the presence of 20 mol% sulfamic acid as the catalyst under ultrasound irradiation (130 W, 20 kHz at 40% amplitude) at ambient conditions; bIsolated yields; cE (environment)-factor calculated for 1st run without considering catalyst as it was reused in the next cycle; dE (environment)-factor calculated for 2nd run considering catalyst-amount as it could not be reused further; TON: Turnover number of the process.

8


Page 9 of 34 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


We herein propose a possible mechanism (Scheme 2) for the ultrasound-assisted sulfamic acid-catalyzed one-pot synthesis of diversely substituted 7-aryl/heteroarylchromeno[4,3d]pyrido[1,2-a]pyrimidin-6(7H)-ones

(4)

from

three-component

reaction

of

4-

hydroxycoumarin (1), aromatic aldehydes (2) and 2-aminopyridine (3) in aqueous ethanol. To get an idea about the initial start-up reaction, we performed a set of two separate reactions between 4-hydroxycoumarin (1; 1.0 equiv) and 4-nitrobenzaldehyde (2-1; 1.0 equiv), and 4nitrobenzaldehyde (2-1; 1.0 equiv) and 2-aminopyrine (3-1; 1.0 equiv) using 20 mol% sulfamic acid as catalyst in 3 mL of aqueous ethanol (1:1) under the influence of ultrasound. We observed that the later reaction (i.e. reaction between 4-nitrobenzaldehyde and 2aminopyridine) did not occur, but the former proceeded rapidly yielding a bis-courmarin derivative [viz. 3,3'-((4-nitrophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one] as the product; the reaction is so fast that we could not isolate the proposed intermediate 6. However, in the presence of 2-aminopyridine (3-1; 1.0 equiv; three-component one-pot reaction) we isolated our desired product 4 instead of a trace amount of bis-coumarin. Based on these experimental outcomes, we hereby proposed that sulfamic acid-activated aldehyde (2) initially undergoes Claisen-Schmidt condensation with 4-hydroxycoumarin (1) in aqueous ethanol under the influence of ultrasound to form a chalcone intermediate 6 (could not be isolated) that is immediately attacked by the nucleophile, 2-aminopyridine (3), through its ring-nitrogen to generate adduct 7. Compound 7 then tautomerizes to 7′, which in turn, participates in a facile intramolecular 6-exo-trig ring-closure under the reaction conditions to generate the cycloadduct 8 (the catalyst is also regenerated in this step) that eventually furnishes the desired product 4 on elimination of water as a green waste (Scheme 2).

9



Page 10 of 34

Scheme 2: Proposed mechanism for the ultrasound-assisted sulfamic acid-catalyzed threecomponent one-pot synthesis of substituted chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)ones (4) at ambient conditions We performed a gram-scale (5 mmol scale) experiment with our model reaction (Table 2; entry 1) in aqueous ethanol under the catalytic influence of sulfamic acid at ambient conditions;

the

large-scale

reaction

furnished

the

target

product,

7-(4-

nitrophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-1), in 91% yield at 25 min. To our delight, the experimental outcomes are almost similar with small-scale (0.25 mmol scale) entry (Table 2, entry 1). In addition, the filtrate containing residual reactants, catalyst and solvent obtained from the final reaction mixture was successfully reused up to the second run in the case of two representative entries (Table 2, entry 1 and 2), viz., reaction between 4-hydroxycoumarin, 4-nitrobenzaldehyde/benzaldehyde, and 2-aminopyridine. The respective desired products, 7-(4-nitrophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)one (4-1) and 7-phenylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-2), were isolated in 86% and 80% yields, respectively, within almost the same time-frame but with somewhat reduced yields compared to the 1st runs. To evaluate green chemistry credentials of this newly developed synthetic method, we estimated diverse green metrics based on the well-established working formulas.64-72 The calculated green credential indices include effective mass yield (EMY), atom economy (AE), atom efficiency (AEf), carbon efficiency (CE), reaction mass efficiency (RME), optimum 10


Page 11 of 34 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


efficiency (OE), mass productivity (MP), mass intensity (MI) and process mass intensity (PMI), E-factor, solvent and water intensity (SI and WI), turn over number (TON) and turn over frequency (TOF) for all the synthesized compounds 4 (4-1‒4-30) both for the 1st and 2nd run (see Supporting Information). The calculated effective mass yield, atom economy and atom efficiency for the method measures to up to 86.73%, 91.89% and 87.98%, respectively. The process shows a good profile of calculated carbon efficiency (72.0 to 96.0%). Reaction mass efficiency (RME) is regarded as the most useful metric to determine the greenness of a process; calculations of RME (63.37 to 86.73% for 1st run, and 60.38 to 82.52% for 2nd run) also support excellent green credential of the present method. Similarly, process mass intensity (PMI) evaluation (73.14 to 49.39 g/g for 1st run, and 73.22 to 49.44 g/g for 2nd run) also corroborates with this fact. The calculated E-factors (g/g) range from 0.58 to 0.15 for 1st run and 0.66 to 0.21 for 2nd run, which convincingly indicate considerable green features of this present method. The turnover number (TON) and turnover frequency (TOF min1) for all the products were found to be in the range of 3.6 to 4.8, and 1.15 to 0.11 min1, respectively. All other estimated parameters are quite in order. The Supporting Information of this article embodies respective green metrics data for all the entries and also their calculations in case of a representative example.

CONCLUSION In conclusion, we have developed an ultrasound-assisted facile, rapid, and highly efficient green synthetic protocol for a new series of pharmaceutically interesting functionalized 7aryl/heteroarylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-ones (4) from the one-pot three component reaction between 4-hydroxycoumarin (1), substituted aromatic aldehydes (2), and 2-aminopyridines (3) in the presence of sulfamic acid as an eco-friendly solid acid-catalyst in aqueous ethanol at ambient conditions. The notable advantages of this present protocol include use of commercially available low-cost starting materials and, eco-friendly catalyst, metal-free one-pot synthesis, energy-efficiency, short reaction times, operational simplicity and

clean

reaction

profiles,

reusability

of

reaction

media,

ease

of

product

isolation/purification without the aid of tedious column chromatography, large-scale synthetic applicability, good to excellent yields, high atom-economy, low E-factor and high turnover number (TON), thereby satisfying several aspects of green and sustainable chemistry.73 All relevant green credentials of the process have been determined and found to be highly 11



Page 12 of 34

satisfied. Exploration of biological activities of this new series of multi-heterocentric organic scaffolds is now under study in our laboratory. EXPERIMENTAL SECTION General Considerations. Infrared spectra were recorded using a Shimadzu (FT-IR 8400S) FT-IR spectrophotometer using KBr disc. 1H and

13

C NMR spectra were collected at 400

MHz and 100 MHz, respectively, on a Bruker DRX spectrometer using DMSO-d6 as solvent. Sonics made ultrasound probe-sonicator (Model: VCX 130) with a frequency of 20 kHz and energy of 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 7-Aryl/heteroaryl-chromeno[4,3-d]pyrido[1,2a]pyrimidin-6(7H)-ones (4): 4-Hydroxycoumarin (1; 0.25 mmol), aromatic aldehydes (2; 0.25 mmol), 2-aminopyridines (3; 0.25 mmol), sulfamic acid (20 mol%; 0.005 g) and 3 mL of aqueous ethanol (1 : 1 v/v) were transferred to an oven-dried glass-vessel in a sequential manner at ambient conditions, and the reaction mixture was then irradiated with ultrasound (130 W, 20 kHz at 40% amplitude) for stipulated time-frame (4-35 min). The progress of the reaction was monitored by TLC. On completion of the reaction, 2 mL of distilled water was added to the resulting reaction mixture when a solid mass precipitated out which was filtered off furnishing the desired products 4 (4-1 – 4-30) in pure form. The structure of each compound was confirmed by analytical as well as spectral studies including FT-IR, 1H-NMR, 13C-NMR and DEPT-135. The spectral and analytical data of all the compounds (4) are given below: 7-(4-Nitrophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one

(4-1).

Off-white

amorphous powder; yield: 94% (87 mg; 0.25 mmol scale); mp = 225-226 C. IR (KBr): max = 3165, 3108, 2914, 1666 (CO), 1603, 1532, 1507, 1489, 1411, 1337, 1277, 1184, 1020, 998, 943, 851, 831, 763, 689, 627, 556, 536, 456 cm1. 1HNMR (400 MHz, DMSO-d6):  = 8.05 (d, 1H, J = 8.8 Hz, Ar-H), 7.92-7.88 (m, 3H, Ar-H), 7.80 (dd, 1H, J = 7.8, 1.2 and 0.8 Hz, ArH), 7.51 (dt, 1H, J = 7.8, 7.4 and 1.2 Hz, Ar-H), 7.35 (d, 1H, J = 8.4 Hz, Ar-H), 7.28-7.25(m, 2H, Ar-H), 7.22 (d, 1H, J = 7.6 Hz, Ar-H), 6.96-6.94 (m, 1H, Ar-H), 6.84 (t, 1H, J = 6.8 and 12


Page 13 of 34 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


6.4 Hz, Ar-H), 6.34 (s, 1H, -CH) ppm.

13

CNMR (100 MHz, DMSO-d6):= 167.95 (CO),

164.35, 153.90, 152.57, 151.50, 145.29, 144.11, 136.06, 131.23, 127.87, 124.18, 123.13 (2C), 123.05, 119.69, 115.59 (2C), 113.39, 112.15, 102.75, 36.75 (CH) ppm. Elemental analysis: calcd (%) for C21H13N3O4: C, 67.92; H, 3.53; N, 11.32; Found: C, 67.76; H, 3.52; N, 11.29. 7-Phenylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one

(4-2).

White

amorphous

powder; yield: 91% (74 mg; 0.25 mmol scale); mp = 211-212 C. IR (KBr): max = 3108, 3060, 2923, 1682 (CO), 1662, 1597, 1542, 1495, 1249, 1106, 1040, 867, 640, 527 cm1. 1

HNMR (400 MHz, DMSO-d6):  = 7.93-7.88 (m, 2H, Ar-H), 7.81 (dd, 1H, J= 7.6 and 1.6

Hz, Ar-H), 7.50 (dt, 1H, J = 7.8, 7.6, 1.6 and 1.2 Hz, Ar-H), 7.26 (d, 2H, J = 8.8 Hz, Ar-H), 7.21 (d, 1H, J = 7.6 Hz, Ar-H), 7.15 (t, 2H, J =7.6 and 7.2 Hz, Ar-H), 7.10-7.04 (m, 2H, ArH), 6.97-6.95 (m, 1H, Ar-H), 6.86-6.83 (m, 1H, Ar-H), 6.27 (s, 1H, -CH) ppm.

13

CNMR

(100 MHz, DMSO-d6):= 167.43 (CO), 164.62, 153.85, 152.47, 144.19, 142.09, 135.96, 131.02, 127.74, 126.65, 124.89, 124.09 (2C), 122.98, 119.70, 115.52 (2C), 113.45, 112.15, 103.49, 36.11 (CH) ppm. Elemental analysis: calcd (%) for C21H14N2O2: C, 77.29; H, 4.32; N, 8.58; Found: C, 77.24; H, 4.33; N, 8.59. 7-(2-Fluorophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one

(4-3).

White

amorphous powder; yield: 96% (82 mg; 0.25 mmlo scale); mp = 112-113 C. IR (KBr) max: = 3180, 3012, 1664 (CO), 1606, 1541, 1486, 1453, 1404, 1328, 1280, 1224, 1183, 1108, 1036, 904, 754, 626 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.91-7.87 (m, 2H, Ar-H), 7.81 (dd, 1H, J = 7.8, 1.6 and 1.2 Hz, Ar-H), 7.48 (dt, 1H, J = 7.8, 7.6, 1.6 and 1.2 Hz, Ar-H), 7.28-7.23 (m, 2H, Ar-H), 7.20 (d, 2H, J = 8.8 Hz, Ar-H), 7.15-7.10 (m, 1H, Ar-H), 7.02-6.96 (m, 1H, Ar-H), 6.96-6.91 (m, 1H, Ar-H), 6.83 (t, 1H, J = 6.8 Hz, Ar-H), 6.32 (s, 1H, -CH) ppm.

13

CNMR (100 MHz, DMSO-d6):= 167.80 (CO), 164.06, 161.80, 159.37, 153.95,

152.43, 144.17, 136.06, 130.98, 130.02 (JCF = 12 Hz), 129.72 (JCF = 52 Hz), 127.16 (JCF = 32 Hz), 124.12, 123.12 (JCF = 92 Hz), 119.90, 115.50, 114.91 (JCF = 88 Hz), 113.44, 112.22, 102.72, 31.92 (-CH) ppm. Elemental analysis: calcd (%) for C21H13FN2O2: C, 73.25; H, 3.81; N, 8.14; Found: C, 73.19; H, 3.80; N, 8.11.

7-(3-Chlorophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one

(4-4).

White

amorphous powder; yield: 93% (84 mg; 0.25 mmol scale); mp = 177-178 C. IR (KBr) max: = 3190, 3085, 2950, 1670 (CO), 1664, 1585, 1520, 1512, 1440, 1310, 1260, 1126, 1040, 980, 13



Page 14 of 34

870, 755, 680, 580, 520, 455 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.92-7.88 (m, 2H, Ar-H), 7.81 (dd, 1H, J = 8.0 and 1.2 Hz, Ar-H), 7.50 (dt, 1H, J = 7.8, 7.6, 1.6 and 1.2 Hz, ArH), 7.26 (d, 2H, J = 8.8 Hz, Ar-H), 7.22 (br. s, 1H, Ar-H), 7.21-7.18 (m, 1H, Ar-H), 7.13 (d, 1H, J = 8.0 Hz, Ar-H), 7.05 (d, 1H, J = 7.6 Hz, Ar-H), 6.96 (d, 1H, J = 9.2 Hz, Ar-H), 6.84 (t, 1H, J = 6.8 Hz, Ar-H), 6.26 (s, 1H, -CH) ppm. 13CNMR (100 MHz, DMSO-d6):= 167.77 (CO), 164.39, 153.86, 152.48, 145.28, 144.07, 136.02, 132.51, 131.05, 129.60, 126.26, 125.50, 124.91, 124.12, 122.95, 119.73, 115.50, 113.36, 112.09, 102.85, 36.06 (-CH) ppm. Elemental analysis: calcd (%) for C21H13ClN2O2: C, 69.91; H, 3.63; N, 7.76; Found: C, 69.84; H, 3.62; N, 7.78.

7-(4-Fluorophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one

(4-5).

White

amorphous powder; yield: 92% (79 mg; 0.25 mmol scale); mp = 224-225 C. IR (KBr): max = 3180, 2925, 1685(CO), 1662, 1603, 1544, 1507, 1408, 1330, 1228, 1184, 1106, 1056, 1037, 998, 860, 760, 678, 555, cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.92-7.87 (m, 3H,Ar-H), 7.80 (dd, 1H, J = 8.0 and 1.2 Hz, Ar-H), 7.49 (dt, 1H, J = 7.6 and 1.6 Hz, Ar-H), 7.24 (d, 2H, J = 8.4 Hz, Ar-H), 7.20 (d, 1H, J = 7.2 Hz, Ar-H), 7.11-7.07 (m, 1H, Ar-H); 6.98-6.94 (m, 2H, Ar-H), 6.85-6.82 (m, 1H, Ar-H), 6.24(s, 1H, -CH) ppm.

13

CNMR (100

MHz, DMSO-d6):= 167.70 (CO), 164.48, 161.31, 158.92, 153.88, 152.49, 144.09, 138.23 (JCF = 12 Hz), 136.04, 130.95, 128.31(JCF = 28 Hz), 124.10, 122.89 (2C), 119.85, 115.45 (2C), 114.24 (JCF = 80 Hz), 113.38, 112.11, 103.37, 35.57 (-CH) ppm. Elemental analysis: calcd (%) for C21H13FN2O2: C, 73.25; H, 3.81; N, 8.14; Found: C, 73.20; H, 3.80; N, 8.12. 7-(4-Bromophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one

(4-6).

White

amorphous powder; yield: 91% (92 mg; 0.25 mmol scale); mp = 240-242 C. IR (KBr): max = 3146, 2916, 1668 (CO), 1597, 1530, 1483, 1406, 1328, 1276, 1195, 1182, 1110, 1009, 764, 627, 487 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.92-7.90 (m, 2H, Ar-H), 7.80 (dd, 1H, J = 7.8, 1.6 and 1.2 Hz, Ar-H), 7.49 (dt, 2H, J = 7.8, 7.6, 1.6 and 1.2 Hz, Ar-H), 7.33 (d, 1H, J = 8.4 Hz, Ar-H), 7.25 (d, 2H, J = 8.8 Hz, Ar-H), 7.21 (d, 1H, J = 7.2 Hz, Ar-H), 7.04 (d, 1H, J = 7.6 Hz, Ar-H), 6.97-6.94 (m, 1H, Ar-H), 6.85-6.82 (m, 1H, Ar-H), 6.21 (s, 1H, -CH) ppm.

13

CNMR (100 MHz, DMSO-d6):= 167.72 (CO), 164.42, 153.88, 152.49, 144.06,

141.93, 136.04, 131.00, 130.51, 128.99, 124.10 (2C), 122.91, 119.79, 117.77, 115.47 (2C),

14


Page 15 of 34 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


113.37, 112.10, 103.05, 35.82 (-CH) ppm. Elemental analysis: calcd (%) for C21H13BrN2O2: C, 62.24; H, 3.23; N, 6.91; Found: C, 62.18; H, 3.22; N, 6.89.

7-(4-Hydroxyphenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-7). Off-white amorphous powder; yield: 91% (78 mg; 0.25 mmol scale); mp = 157-158 C. IR (KBr): max = 3500, 3154, 2925, 1668 (CO), 1607, 1559, 1509, 1444, 1389, 1417, 1232, 1187, 1108, 1057, 953, 905, 859, 760, 626, 559, 544, 464 cm1. 1HNMR (400 MHz, DMSO-d6):  = 8.92 (br. s, Ar-OH), 7.92-7.88 (m, 2H, Ar-H), 7.79 (dd, 1H, J = 8.0, 1.2 Hz, Ar-H), 7.49-7.45 (m, 1H, Ar-H); 7.23 (d, 2H, J = 8.0 Hz, Ar-H), 7.19 (d, 1H, J = 7.6 Hz, Ar-H), 6.96-6.94 (m, 1H, Ar-H), 6.87-6.82 (m, 2H, Ar-H), 6.54 (d, 2H, J = 8.4 Hz, Ar-H), 6.15 (s, 1H, -CH) ppm. 13

CNMR (100 MHz, DMSO-d6):= 167.50 (CO), 164.55, 154.59, 153.92, 152.44, 144.04,

136.13, 132.24, 130.74, 127.50 (2C), 124.05, 122.77, 119.98, 115.37, 114.46 (2C), 113.33, 112.12, 103.79, 35.28 (-CH) ppm. Elemental analysis: calcd (%) for C21H14N2O3: C, 73.68; H, 4.12; N, 8.18; Found: C, 73.70; H, 4.11; N, 8.16.

7-(3,4-Dihydroxyphenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-8). Grey amorphous powder; yield: 92% (83 mg; 0.25 mmol scale); mp = 180-181 C. IR (KBr): max = 3085, 2980, 1669 (CO), 1585, 1530, 1480, 1310, 1230, 1190, 1030, 925, 920, 760, 750, 666, 510, 440cm1. 1HNMR (400 MHz, DMSO-d6):  = 8.47 (br. s, 1H, Ar-OH), 8.31 (br. s, 1H, Ar-OH), 7.91-7.87 (m, 2H, Ar-H), 7.80 (dd, 1H, J = 7.6 and 1.2 Hz, Ar-H), 7.48 (dt, 1H, J = 7.6 and 1.6 Hz, Ar-H), 7.23 (d, 2H, J = 8.0 Hz, Ar-H), 7.20 (d, 1H,J = 7.6 Hz, Ar-H), 6.95 (d, 1H, J = 8.8 Hz, Ar-H), 6.83 (t, 1H, J = 6.8 and 6.4 Hz, Ar-H), 6.52-6.48 (m, 1H, ArH), 6.32 (d, 1H, J = 8.4 Hz, Ar-H), 6.11 (s, 1H, -CH) ppm.

13

CNMR (100 MHz, DMSO-

d6):= 167.56 (CO), 164.61, 153.96, 152.45, 144.44, 144.01, 142.45, 136.20, 133.06, 130.73, 124.10, 122.78, 120.06, 117.32, 115.37, 114.91, 114.35, 113.31, 112.13, 103.79, 35.34 (-CH) ppm. Elemental analysis: calcd (%) for C21H14N2O4: C, 70.39; H, 3.94; N, 7.82; Found: C, 70.26; H, 3.93; N, 7.79. 7-(2,4-Dichlorophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-9). White amorphous powder; yield: 95% (94 mg; 0.25 mmol scale); mp = 136-138 C. IR (KBr): max = 3166, 3035, 2970, 1670 (CO), 1595, 1525, 1490, 1301, 1270, 1170, 1080, 990, 810, 760, 602, 510, 490, 460 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.92-7.88 (m, 2H,Ar-H), 7.80 (dd, 1H, J = 7.6 and 1.2 Hz, Ar-H), 7.48 (dt, 1H, J = 8.0, 7.6 and 1.6 Hz, Ar-H), 7.39-7.35 15



(m, 1H, Ar-H), 7.27 (dd, 1H, J = 8.0 and 2.0 Hz, Ar-H), 7.24 (s, 1H, Ar-H), 7.23-7.19 (m, 2H, Ar-H), 6.97-6.94 (m, 1H, Ar-H), 6.86-6.82 (m, 1H, Ar-H), 6.11 (s, 1H, -CH) ppm. 13

CNMR (100 MHz, DMSO-d6):= 167.73 (CO), 163.76, 153.85, 152.38, 144.10, 139.63,

135.99, 133.41, 131.62, 130.93, 130.56, 128.64, 126.09, 124.03, 122.94, 119.73, 115.46, 113.39, 112.11, 102.38, 35.78 (-CH) ppm. Elemental analysis: calcd (%) for C21H12Cl2N2O2: C, 63.82; H, 3.06; N, 7.09; Found: C, 63.68; H, 3.05; N, 7.07.

7-(4-Methoxyphenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-10). White amorphous powder; yield: 92% (81 mg; 0.25 mmol scale); mp = 206-207 C. IR (KBr): max = 3150, 3095, 2924, 2853, 1677 (CO), 1662, 1605, 1555, 1541, 1508, 1466, 1450, 1378, 1276, 1183, 1036, 947, 904, 819, 759, 723, 678, 558, 466 cm1. 1HNMR (400 MHz, DMSOd6):  = 7.92-7.88 (m, 2H, Ar-H), 7.81 (dd, 1H, J = 7.8, 1.6 and 1.2 Hz, Ar-H), 7.50 (dt, 1H, J = 7.6 and 1.6 Hz, Ar-H), 7.25 (d, 2H, J = 8.0 Hz, Ar-H), 7.21 (dd, 1H, J = 7.6 and 0.8 Hz, ArH), 6.99-6.95 (m, 2H, Ar-H), 6.97 (dt, 1H, J = 6.8 and 0.6 Hz, Ar-H), 6.72 (d, 2H, J = 8.8 Hz, Ar-H), 6.21 (s, 1H, -CH), 3.66 (s, 3H, Ar-OCH3) ppm. 13CNMR (100 MHz, DMSO-d6):= 167.25 (CO), 164.61, 156.87, 153.85, 152.44, 144.18, 135.96, 133.70, 131.00, 127.63, 124.06 (2C), 122.98, 119.66, 115.50 (2C), 113.44, 113.17, 112.15, 103.78, 54.88(Ar-OCH3), 35.34 (CH) ppm. Elemental analysis: calcd (%) for C22H16N2O3: C, 74.15; H, 4.53; N, 7.86; Found: C, 74.06; H, 4.52; N, 7.89. 7-(m-Tolyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-11). White amorphous powder; yield: 91% (78 mg; 0.25 mmol scale); mp = 137-138 C. IR (KBr): max = 3180, 3095, 3035, 2920, 1668 (CO), 1650, 1590, 1520, 1430, 1390, 1280, 1166, 1010, 995, 840, 750, 610, 580, 420 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.92-7.90 (m, 2H, Ar-H), 7.79 (dd, 1H, J = 7.8, 1.6 and 1.2 Hz, Ar-H), 7.50-7.46 (m, 2H, Ar-H), 7.24 (d, 2H, J = 7.6 Hz, Ar-H), 7.19 (d, 1H, J = 7.4 Hz, Ar-H), 7.04-7.00 (m, 1H, Ar-H), 6.95 (dd, 1H, J = 9.6 and 0.8 Hz, Ar-H), 6.89-6.87 (m, 2H, Ar-H), 6.22 (s, 1H, -CH), 2.16 (s, 3H, Ar-CH3) ppm. 13CNMR (100 MHz, DMSO-d6):= 167.63 (CO), 164.52, 153.95, 152.45, 144.01, 142.44, 136.21, 135.20, 130.82, 127.51, 127.22, 125.52, 124.10, 123.87, 122.82, 119.93, 115.41, 113.30, 112.12, 103.46, 36.01 (-CH), 21.26 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C22H16N2O2: C, 77.63; H, 4.74; N, 8.23; Found: C, 77.59; H, 4.73; N, 8.25.

16


Page 16 of 34

Page 17 of 34 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


7-(p-Tolyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-12). White amorphous powder; yield: 90% (77 mg; 0.25 mmol scale); mp = 229-230 C. IR (KBr): max = 3166, 3070, 3015, 2930, 2920, 1674 (CO), 1668, 1644, 1565, 1558, 1475, 1310, 1235, 1125, 1010, 970, 830, 790, 740, 605, 515, 465 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.91-7.88 (m, 2H, Ar-H), 7.79 (d, 1H, J = 7.2 Hz, Ar-H), 7.48 (t, 1H, J = 7.2 Hz, Ar-H), 7.24 (d, 2H, J = 8.4 Hz, Ar-H), 7.20 (d, 1H, J = 7.2 Hz, Ar-H), 6.96-6.95 (m, 4H, Ar-H), 6.85-6.82 (m, 1H, ArH), 6.21 (s, 1H, -CH), 2.19 (s, 3H, Ar-CH3) ppm.

13

CNMR (100 MHz, DMSO-d6):=

167.68 (CO), 164.64, 153.94, 152.51, 144.13, 139.22, 136.09, 133.54, 130.91, 128.32, 126.60 (2C), 124.13, 122.91 (2C), 119.97, 115.47, 113.41, 112.18, 103.58, 35.79 (-CH), 20.53 (ArCH3) ppm. Elemental analysis: calcd (%) for C22H16N2O2: C, 77.63; H, 4.74; N, 8.23; Found: C, 77.53; H, 4.73; N, 8.26.

7-(4-(Dimethylamino)phenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-13). Off-white amorphous powder; yield: 70% (65 mg; 0.25 mmol scale); mp = 182-183 C. IR (KBr): max = 3035, 3020, 2939, 2920, 1665 (CO), 1658, 1583, 1515, 1480, 1380, 1210, 1120, 1020, 985, 810, 750, 690, 626, 525, 495 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.80 (dd, 2H, J = 7.2 and 1.2 Hz, Ar-H), 7.50 (dt, 2H, J = 7.8 and 1.2 Hz, Ar-H), 7.39 (d, 2H, J = 8.8 Hz, Ar-H), 7.26 (d, 4H, J = 8.8 Hz, Ar-H), 7.22 (d, 2H, J = 7.6 Hz, Ar-H), 6.28 (s, 1H, -CH), 3.12 (s, 6H, 2 × -NCH3) ppm. 13CNMR (100 MHz, DMSO-d6):= 167.67 (CO), 164.54, 152.54 (2C), 143.04, 140.82, 131.22 (2C), 128.21 (2C), 124.15 (2C), 123.09 (2C), 119.67, 119.54, 115.62 (2C), 103.09 (2C), 45.52 (2 × -NCH3), 35.98 (-CH) ppm. Elemental analysis: calcd (%) for C23H19N3O2: C, 74.78; H, 5.18; N, 11.37; Found: C, 74.68; H, 5.19; N, 11.35.

7-(3-Hydroxy-4-methoxyphenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one

(4-

14). White amorphous powder; yield: 93% (86 mg; 0.25 mmol scale); mp = 189-190 C. IR (KBr): max = 3610, 3190, 3015, 3004, 2910, 1666 (CO), 1625, 1590, 1510, 1485, 1255, 1246, 1166, 1035, 1029, 975, 920, 810, 755, 751, 660, 515, 485 cm1. 1HNMR (400 MHz, DMSO-d6):  = 8.56 (br s, 1H, Ar-OH), 7.90-7.89 (m, 1H, Ar-H), 7.81 (dd, 1H, J = 7.8, 1.2 and 0.8 Hz, Ar-H), 7.48 (dt, 1H, J = 7.6 and 1.6 Hz, Ar-H), 7.24 (d, 2H, J = 7.6 Hz, Ar-H), 7.20 (d, 1H, J = 7.6 Hz, Ar-H), 6.95 (d, 1H, J = 9.2 Hz, Ar-H), 6.83 (t, 1H, J = 6.8, 6.4Hz, Ar-H), 6.68 (d, 1H, J = 8.4 Hz, Ar-H), 6.56 (br s, 1H, Ar-H), 6.46 (d, 1H, J = 8.4 Hz, Ar-H), 17



Page 18 of 34

6.15 (s, 1H, -CH), 3.66 (s, 3H, Ar-OCH3) ppm. 13CNMR (100 MHz, DMSO-d6):= 167.71 (CO), 164.71, 153.95, 152.51, 145.95, 145.16, 144.14, 136.08, 134.99, 130.89, 124.16, 122.91, 120.04, 117.22, 115.46, 114.48, 113.42, 112.20, 112.11, 103.70, 55.76 (Ar-OCH3), 35.47 (-CH) ppm. Elemental analysis: calcd (%) for C22H16N2O4: C, 70.96; H, 4.33; N, 7.52; Found: C, 70.91; H, 4.32; N, 7.54. 7-(3,4-Dimethoxyphenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one

(4-15).

White amorphous powder; yield: 93% (90 mg; 0.25 mmol scale); mp = 215-216 C. IR (KBr): max = 3157, 3101, 2931, 2836, 1665 (CO), 1601, 1532, 1510, 1450, 1408, 1378, 1210, 1181, 1139, 996, 924, 857, 760, 772, 629, 550, 455 cm1. 1HNMR (400 MHz, DMSOd6):  = 7.91-7.87 (m, 2H, Ar-H), 7.79 (dd, 1H, J = 7.6 and 1.6 Hz, Ar-H), 7.48 (dt, 1H, J = 7.6 and 1.6 Hz, Ar-H), 7.23 (d, 2H, J = 7.6 Hz, Ar-H), 7.19 (dd, 1H, J = 7.6 and 0.8 Hz, ArH), 6.96-6.94 (m, 1H, Ar-H), 6.84 (dt, 1H, J = 6.8, 6.6, 0.8 and 0.4 Hz, Ar-H), 6.74 (d, 1H, J = 8.0 Hz, Ar-H), 6.65-6.60 (m, 1H, Ar-H), 6.19 (s, 1H, -CH), 3.66 (s, 3H, Ar-OCH3), 3.50 (s, 3H, Ar-OCH3) ppm.

13

CNMR (100 MHz, DMSO-d6):= 167.70 (CO), 164.59, 153.94,

152.47, 148.23, 146.61, 144.12, 136.10, 134.90, 130.88, 124.10, 122.90, 119.96, 118.96, 115.46, 113.39, 112.18, 111.58, 111.46, 103.67, 55.53 (Ar-OCH3), 55.49 (Ar-OCH3), 35.74 (-CH) ppm. Elemental analysis: calcd (%) for C23H18N2O4: C, 71.49; H, 4.70; N, 7.25; Found: C, 71.51; H, 4.68; N, 7.27.

7-(Benzo[d][1,3]dioxol-5-yl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one

(4-16).

White amorphous powder; yield: 92% (85 mg; 0.25 mmol scale); mp = 218-219 C. IR (KBr): max = 3164, 3090, 3025, 2955, 1672 (CO), 1666, 1583, 1535, 1510, 1427, 1310, 1250, 1173, 1015, 909, 801, 710, 666, 525, 485 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.91-7.87 (m, 2H, Ar-H), 7.80 (dd, 1H, J = 7.6 and 1.2 Hz, Ar-H), 7.48 (dt, 1H, J = 7.8, 7.6, 1.6 and 1.2 Hz, Ar-H), 7.24 (d, 2H, J = 7.6 Hz, Ar-H), 7.20 (d, 1H, J = 7.6 Hz, Ar-H), 6.95 (d, 1H, J = 9.2 Hz, Ar-H), 6.83 (t, 1H, J = 6.8 and 6.4 Hz, Ar-H), 6.68 (d, 1H, J = 8.0 Hz, ArH), 6.57-6.56 (m, 1H, Ar-H), 6.17 (s, 1H, -CH), 5.89 (s, 2H, -OCH2O-) ppm. 13CNMR (100 MHz, DMSO-d6):= 167.72 (CO), 164.57, 153.93, 152.50, 146.96, 144.62, 144.13, 136.33, 136.08, 130.98, 124.14, 122.95, 119.91, 119.39, 115.50, 113.42, 112.18, 107.53, 107.30, 103.62, 100.48 (-OCH2O), 35.92 (-CH) ppm. Elemental analysis: calcd (%) for C22H14N2O4: C, 71.35; H, 3.81; N, 7.56; Found: C, 71.29; H, 3.80; N, 7.54. 18


Page 19 of 34 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


4-(6-Oxo-6,7-dihydrochromeno[4,3-d]pyrido[1,2-a]pyrimidin-7-yl)benzonitrile

(4-17).

White amorphous powder; yield: 97% (85 mg; 0.25 mmol scale); mp: = 228-229 C. IR (KBr): max = 3153, 2902, 2227 (CN), 1665 (CO), 1592, 1525, 1406, 1276, 1182, 994, 905, 858, 761, 677, 625, 551, 476, 420 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.90-7.88 (m, 2H, Ar-H), 7.79 (d, 1H, J = 7.2 Hz, Ar-H), 7.62 (d, 1H, J = 8.0 Hz, Ar-H), 7.50 (t, 1H, J = 8.0 and 7.2 Hz, Ar-H), 7.28-7.25 (m, 4H, Ar-H), 7.21 (d, 1H, J = 7.2 Hz, Ar-H), 6.96-6.94 (m, 1H, Ar-H), 6.84 (t, 1H, J = 6.8, 6.4 Hz, Ar-H), 6.30 (s, 1H, -CH) ppm. 13CNMR (100 MHz, DMSO-d6):= 167.94 (CO), 164.45, 153.94, 152.59, 149.02, 144.16, 136.07, 131.83, 131.23, 127.78 (2C), 124.20, 123.07, 119.73, 119.31 (-CN), 115.60 (2C), 113.44, 112.19, 107.73, 102.71, 36.74 (-CH) ppm. Elemental analysis: calcd (%) for C22H13N3O2: C, 75.20; H, 3.73; N, 11.96; Found: C, 75.17; H, 3.74; N, 11.93.

7-(4-(Trifluoromethyl)phenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-18). White amorphous powder; yield: 94% (93 mg; 0.25 mmol scale); mp: = 235-236 C. IR (KBr): max = 3156, 2913, 2852, 1667 (CO), 1618, 1597, 1408, 1322, 1201, 1158, 1116, 1037, 1017, 906, 860, 763, 661, 555, 480 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.927.88 (m, 2H, Ar-H), 7.79 (dd, 1H, J = 7.8, 1.6 and 1.2 Hz, Ar-H), 7.53-7.48 (m, 3H, Ar-H), 7.30-7.27 (m, 2H, Ar-H), 7.25-7.20 (m, 2H, Ar-H), 6.96-6.94 (m, 1H, Ar-H), 6.84 (t, 1H, J = 6.8 and 6.4 Hz, Ar-H), 6.31 (s, 1H, -CH) ppm. 13CNMR (100 MHz, DMSO-d6):= 167.88 (CO), 164.47, 153.93, 152.56, 147.64, 144.13, 136.07, 131.15 (2C), 127.38, 124.74, 124.70, 124.18, 123.02 (2C), 119.77, 115.56 (2C), 113.41, 112.18, 102.93, 36.40 (-CH) ppm. Elemental analysis: calcd (%) for C22H13F3N2O2: C, 67.01; H, 3.32; N, 7.10; Found: C, 66.92; H, 3.31; N, 7.08.

7-(Furan-2-yl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one

(4-19).

Pale-brown

amorphous powder; yield: 92% (73 mg; 0.25 mmol scale); mp: = 175-176 C. IR (KBr): max = 3190, 3114, 2990, 1685 (CO), 1678, 1620, 1590, 1525, 1460, 1340, 1295, 1230, 1166, 1080, 1002, 920, 802, 750, 666, 530, 440 cm1. 1HNMR (400 MHz, DMSO-d6): = 7.917.87 (m, 2H, Ar-H), 7.82 (dd, 1H, J = 7.8 and 1.2 Hz, Ar-H), 7.51-7.47 (m, 1H, Ar-H), 7.33 (d, 1H, J = 0.8 Hz, Ar-H), 7.23 (d, 2H, J = 7.6 Hz, Ar-H), 6.96-6.94 (m, 1H, Ar-H), 6.85-6.82 (m, 1H, Ar-H), 6.24-6.22 (m, 1H, Ar-H), 6.18 (br s, 1H, -CH), 5.89-5.88 (m, 1H, Ar-H) ppm. 19



Page 20 of 34

13

CNMR (100 MHz, DMSO-d6):= 167.88 (CO), 164.16, 155.11, 153.97, 152.50, 144.13,

140.56, 136.12, 131.08, 124.18, 123.00, 119.85, 115.52, 113.40, 112.20, 109.99, 105.20, 101.85, 31.67 (-CH) ppm. Elemental analysis: calcd (%) for C19H12N2O3: C, 72.15; H, 3.82; N, 8.86; Found: C, 72.05; H, 3.81; N, 8.83.

4-(6-Oxo-6,7-dihydrochromeno[4,3-d]pyrido[1,2-a]pyrimidin-7-yl)benzaldehyde (4-20). White amorphous powder; yield: 96% (85 mg; 0.25 mmol scale); mp: = 215-216 C. IR (KBr): max = 3185, 2911, 2831, 2740, 1701 (CHO), 1680 (CO), 1663, 1559, 1542, 1404, 1326, 1217, 1183, 1038, 1024, 943, 864, 761, 544, 475 cm1. 1HNMR (400 MHz, DMSOd6):  = 9.89 (s, 1H, Ar-CHO), 7.92-7.88 (m, 2H, Ar-H), 7.81 (dd, 1H, J = 7.6 and 1.2 Hz, Ar-H), 7.72 (d, 1H, J = 8.4 Hz, Ar-H), 7.54-7.49 (m, 2H, Ar-H), 7.32 (d, 1H, J = 8.0 Hz, ArH), 7.29-7.25 (m, 2H, Ar-H), 7.22 (d, 1H, J = 7.6 Hz, Ar-H), 6.97-6.93 (m, 1H, Ar-H), 6.84 (t, 1H, J = 6.8 Hz, Ar-H), 6.34 (s, 1H, -CH) ppm.

13


192.46 (-CHO), 167.59 (CO), 164.42, 153.82, 152.50, 150.19, 144.15, 135.93, 133.78, 131.17, 129.31, 127.38, 124.11, 123.04 (2C), 119.55, 115.57 (2C), 113.42, 112.12, 103.04, 36.76 (-CH) ppm. Elemental analysis: calcd (%) for C22H14N2O3: C, 74.57; H, 3.98; N, 7.91; Found: C, 74.52; H, 3.97; N, 7.93.

11-Methyl-7-(4-nitrophenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one

(4-21).

Pale yellow amorphous powder; yield: 95% (91 mg; 0.25 mmol scale); mp = 240-241 C. IR (KBr): max = 3174, 2908, 1664 (CO), 1603, 1534, 1508, 1411, 1338, 1276, 1183, 1109, 1037, 906, 850, 763, 679, 557, 454 cm1. 1HNMR (400 MHz, DMSO-d6):  = 8.07 (d, 1H, J = 8.4 Hz, Ar-H), 7.82-7.79 (m, 3H, Ar-H), 7.52 (t, 2H, J = 7.6 and 7.2 Hz, Ar-H), 7.37 (d, 1H, J = 8.4 Hz, Ar-H), 7.28 (d, 1H, J = 8.0 Hz, Ar-H), 7.24 (t, 2H, J = 7.6 Hz, Ar-H), 6.736.69 (m, 1H, Ar-H), 6.36 (s, 1H, -CH), 2.30 (s, 3H, Ar-CH3) ppm.

13

CNMR (100 MHz,

DMSO-d6):=167.95 (CO), 164.35, 156.34, 153.48, 152.56, 151.50, 145.28, 135.19, 131.22, 127.86, 124.18, 123.12 (2C), 123.04, 119.69, 115.58 (2C), 114.13, 111.86, 102.75, 36.75 (CH), 21.37 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C22H15N3O4: C, 68.57; H, 3.92; N, 10.90; Found: C, 68.51; H, 3.90; N, 10.93.

7-(4-Methoxyphenyl)-11-methylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one

(4-

22). White amorphous powder; yield: 89% (82 mg; 0.25 mmol scale); mp = 213-214 C. IR 20


Page 21 of 34 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


(KBr): max = 3166, 1663 (CO), 1601, 1529, 1508, 1408, 1363, 1242, 1181, 1035, 905, 761, 679, 556 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.83 (dd, 2H, J = 7.8, 1.6 and 1.2 Hz, Ar-H), 7.80 (d, 1H, J = 6.4 Hz, Ar-H), 7.54-7.49 (m, 2H, Ar-H), 7.29 (br s, 1H, Ar-H), 7.27 (br s, 1H, Ar-H), 7.24 (d, 1H, J = 7.2 Hz, Ar-H), 7.01 (d, 1H, J = 8.4 Hz, Ar-H), 6.74 (d, 2H, J = 8.4 Hz, -CH), 6.23 (br s, 1H, -CH), 3.68 (s, 3H, Ar-OCH3), 2.31 (s, 3H, Ar-CH3) ppm. 13

CNMR (100 MHz, DMSO-d6):= 166.89 (CO), 164.63, 156.93, 156.40, 153.45, 152.39,

135.15, 133.32, 131.13, 127.64 (2C), 124.02, 123.09, 119.36, 115.57 (2C), 114.14, 113.21, 111.88, 103.87, 54.88, 35.32 (-CH), 21.38 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C23H18N2O3: C, 74.58; H, 4.90; N, 7.56; Found: C, 74.49; H, 4.89; N, 7.58.

7-(Benzo[d][1,3]dioxol-5-yl)-11-methylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)one (4-23). White amorphous powder; yield: 74% (76 mg; 0.25 mmol scale); mp = 127-128 

C. IR (KBr): max = 3141, 2924, 1661 (CO), 1600, 1530, 1483, 1431, 1409, 1364, 1231,

1208, 1183, 1037, 938, 760, 679, 557 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.82-7.79 (m, 3H, Ar-H), 7.51-7.47 (m, 1H, Ar-H), 7.24 (d, 2H, J = 7.6 Hz, Ar-H), 7.21 (d, 1H, J = 7.6 Hz, Ar-H), 6.73 (d, 1H, J = 5.2 Hz, Ar-H), 6.69 (d, 1H, J = 8.0 Hz, Ar-H), 6.57 (br s, 1H, ArH), 6.17 (s, 1H, -CH), 5.90 (s, 2H, -OCH2O-), 2.31 (s, 3H, Ar-CH3) ppm.

13

CNMR (100

MHz, DMSO-d6):= 167.67 (CO), 164.50, 156.36, 153.49, 152.48, 146.92, 144.58, 136.34, 135.22, 130.91, 124.10, 122.88, 119.90, 119.35, 115.46, 114.15, 111.87, 107.49, 107.27, 103.59, 100.44 (-OCH2O-), 35.89 (-CH), 21.39 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C23H16N2O4: C, 71.87; H, 4.20; N, 7.29; Found: C, 71.81; H, 4.19; N, 7.31.

7-(4-(Dimethylamino)phenyl)-11-methylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)one (4-24). Pale pinkish amorphous powder; yield: 84% (80 mg; 0.25 mmol scale); mp = 196-197 C. IR (KBr): max = 3167, 1662 (CO), 1603, 1532, 1411, 1362, 1180, 1108,, 1033, 904, 812, 760, 678, 555 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.80 (d, 2H, J = 6.4 Hz, Ar-H), 7.72 (br s, 1H, Ar-H), 7.48 (dt, 2H, J = 8.0, 7.6 and 1.6 Hz, Ar-H), 7.24 (d, 2H, J = 7.6 Hz, Ar-H), 7.20 (d, 1H, J = 7.2 Hz, Ar-H), 6.91 (d, 1H, J = 8.4 Hz, Ar-H), 6.72-6.69 (m, 1H, Ar-H), 6.59 (d, 1H, J = 8.8 Hz, Ar-H), 6.17 (s, 1H, -CH), 2.80 (s, 6H, 2 × -NCH3), 2.30 (s, 3H, Ar-CH3) ppm.

13

CNMR (100 MHz, DMSO-d6):= 167.54 (CO), 164.60, 156.02,

153.71, 152.46, 147.92, 135.65, 130.74 (2C), 127.24, 124.06, 122.79 (2C), 120.03, 115.39 (2C), 114.12, 112.75, 111.72, 103.82, 40.72 (2 × -NCH3) 35.19 (-CH), 21.36 (Ar-CH3) ppm. 21



Elemental analysis: calcd (%) for C24H21N3O2: C, 75.18; H, 5.52; N, 10.96; Found: C, 75.22; H, 5.50; N, 10.93.

7-(2-Fluorophenyl)-11-methylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-25). White amorphous powder; yield: 83% (74 mg; 0.25 mmol scale); mp = 127-128 C. IR (KBr): max = 3181, 1665 (CO), 1607, 1556, 1538, 1486, 1453, 1404, 1224, 1183, 1108, 1038, 755, 516 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.83-7.79 (m, 3H, Ar-H), 7.49 (dt, 1H, J = 7.6 and 1.6 Hz, Ar-H), 7.24 (d, 1H, J = 2.8 Hz, Ar-H), 7.23-7.20 (m, 2H, Ar-H), 7.16-7.11 (m, 1H, Ar-H), 7.01 (t, 1H, J = 7.6 and 6.8 Hz, Ar-H), 6.97-6.92 (m, 1H, Ar-H), 6.73-6.69 (m, 1H, Ar-H), 6.33 (s, 1H, -CH), 2.31 (s, 3H, Ar-CH3) ppm. 13CNMR (100 MHz, DMSO-d6):= 167.71 (CO), 163.95, 161.75, 159.31, 156.34, 153.50, 152.39, 135.22, 130.88, 129.98 (JCF = 16 Hz), 129.71 (JCF = 52 Hz), 127.06 (JCF = 32 Hz), 124.06, 123.04 (JCF = 104 Hz), 122.91, 119.87, 115.43, 114.83 (JCF = 88 Hz), 114.15, 111.85, 102.66, 31.86 (CH), 21.37 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C22H15FN2O2: C, 73.73; H, 4.22; N, 7.82; Found: C, 73.68; H, 4.21; N, 7.80.

7-(4-Fluorophenyl)-11-methylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-26). White amorphous powder; yield: 95% (85 mg; 0.25 mmol scale); mp = 236-237 C. IR (KBr): max = 3192, 2927, 1687 (CO), 1655, 1636, 1615, 1604, 1556, 1405, 1366, 1330, 1301, 1280, 1228, 1183, 1105, 1059, 1035, 1020, 906, 860, 793, 760, 681, 554, 448 cm1. 1

HNMR (400 MHz, DMSO-d6):  = 7.82-7.79 (m, 2H, Ar-H), 7.52-7.48 (m, 2H, Ar-H), 7.25

(d, 2H, J = 8.4 Hz, Ar-H), 7.21 (d, 1H, J = 8.0 Hz, Ar-H), 7.11-7.08 (m, 2H, Ar-H), 6.96 (t, 1H, J = 9.2 and 8.8 Hz, Ar-H), 6.73-6.70 (m, 1H, Ar-H), 6.24 (s, 1H, -CH), 2.31 (s, 3H, ArCH3) ppm.

13

CNMR (100 MHz, DMSO-d6):= 167.72 (CO), 164.48, 161.32, 158.94,

156.37, 153.48, 152.51, 138.24, 135.21, 130.97, 128.35, 128.27, 124.12, 122.91, 119.86, 115.47, 114.37, 114.15, 111.87, 103.38, 35.57 (-CH), 21.39 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C22H15FN2O2: C, 73.73; H, 4.22; N, 7.82; Found: C, 73.66; H, 4.21; N, 7.80.

11-Methyl-7-(4-(trifluoromethyl)phenyl)chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)one (4-27). White amorphous powder; Yield: 93% (95 mg; 0.25 mmol scale); mp = 250-251 

C. IR (KBr): max = 3170, 2917, 1667 (CO), 1617, 1601, 1534, 1408, 1321, 1276, 1117, 22


Page 22 of 34

Page 23 of 34 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


1068, 1017, 906, 858, 760, 622, 555, 453 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.827.79 (m, 3H, Ar-H), 7.54-7.51 (m, 3H, Ar-H), 7.31 (d, 1H, J = 8.0 Hz, Ar-H), 7.28 (br s, 1H, Ar-H), 7.26 (d, 1H, J = 4.0 Hz, Ar-H), 7.22 (d, 1H, J = 7.2 Hz, Ar-H), 6.73-6.69 (m, 1H, ArH), 6.33 (br s, 1H, -CH), 2.30 (s, 3H, Ar-CH3) ppm.

13


167.85 (CO), 164.43, 156.32, 153.49, 152.55, 147.63, 135.22, 131.11, 127.36, 125.98, 125.88, 125.57, 124.69(JCF = 12 Hz), 124.15, 123.28, 122.97, 119.76, 115.54, 114.12, 111.85, 102.91, 36.37 (-CH), 21.37 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C23H15F3N2O2: C, 67.65; H, 3.70; N, 6.86; Found: C, 67.60; H, 3.71; N, 6.84.

4-(11-Methyl-6-oxo-6,7-dihydrochromeno[4,3-d]pyrido[1,2-a]pyrimidin-7yl)benzonitrile (4-28). White amorphous powder; yield: 70% (64 mg; 0.25 mmol scale); mp = 218-219 C. IR (KBr): max = 3178, 2224 (CN), 1664 (CO), 1602, 1533, 1408, 1364, 1276, 1182, 1108, 1036, 905, 857, 765, 678, 559, 517 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.81-7.79 (m, 3H, Ar-H), 7.63 (d, 1H, J = 8.4 Hz, Ar-H), 7.54-7.49 (m, 2H, Ar-H), 7.27 (d, 3H, J = 8.4 Hz, Ar-H), 7.23 (dt, 1H, J = 7.8, 7.2, 1.2 and 0.8 Hz, Ar-H), 6.73 (br s, 1H, ArH), 6.31 (s, 1H, -CH), 2.32 (s, 3H, Ar-CH3) ppm.

13


167.86 (CO), 164.36, 156.35, 153.48, 152.55, 148.98, 135.24, 131.78 (2C), 131.17, 127.72, 124.14, 123.00, 119.68, 119.27 (-CN), 115.55 (2C), 114.14, 111.85, 107.66, 102.65, 36.68 (CH), 21.39 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C23H15N3O2: C, 75.60; H, 4.14; N, 11.50; Found: C, 75.56; H, 4.13; N, 11.48.

7-(Furan-2-yl)-11-methylchromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-one (4-29). Offwhite amorphous powder; yield: 81% (67 mg; 0.25 mmol scale); mp = 188-189 C. IR (KBr): max = 3118, 1682 (CO), 1653, 1613, 1593, 1556, 1533, 1407, 1348, 1281, 1219, 1189, 1105, 1039, 900, 793, 773, 550, 451 cm1. 1HNMR (400 MHz, DMSO-d6):  = 7.84-7.78 (m, 3H, Ar-H), 7.49 (dt, 1H, J = 7.8, 7.6, 1.6 and 1.2 Hz, Ar-H), 7.35 (s, 1H, Ar-H), 7.24 (d, 2H, J = 8.0 Hz, Ar-H), 6.73-6.70 (m, 1H, Ar-H), 6.25-6.23 (m, 1H, Ar-H), 6.20 (br s, 1H, -CH), 5.89 (br s, 1H, Ar-H), 2.31 (s, 3H, Ar-CH3) ppm.

13

CNMR (100 MHz, DMSO-d6):= 167.80

(CO), 164.07, 156.30, 155.09, 153.50, 152.46, 140.49, 135.25, 130.99, 124.13, 122.90, 119.82, 115.45, 114.13, 111.84, 109.92, 105.13, 101.80, 31.61 (-CH), 21.37 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C20H14N2O3: C, 72.72; H, 4.27; N, 8.48; Found: C, 72.65; H, 4.26; N, 8.46. 23



4-(11-Methyl-6-oxo-6,7-dihydrochromeno[4,3-d]pyrido[1,2-a]pyrimidin-7yl)benzaldehyde (4-30). Off-white amorphous powder; yield: 91% (83 mg; 0.25 mmol scale); mp = 220-221 C. IR (KBr): max = 3153, 2908, 1705 (CHO), 1659 (CO), 1597, 1530, 1408, 1363, 1276, 1215, 1182, 1108, 1036, 905, 812, 759, 677, 554, 515, 453 cm1. 1HNMR (400 MHz, DMSO-d6):  = 9.90 (s, 1H, Ar-CHO), 7.82-7.79 (m, 3H, Ar-H), 7.73 (d, 1H, J = 8.4 Hz, Ar-H), 7.52 (dt, 2H, J = 7.8, 7.6, 1.6 and 1.2 Hz, Ar-H), 7.32 (d, 1H, J = 8.0 Hz, ArH), 7.27 (d, 1H, J = 8.4 Hz, Ar-H), 7.23 (t, 2H, J = 7.6 and 7.2 Hz, Ar-H), 6.73-6.70 (m, 1H, Ar-H), 6.34 (s, 1H, -CH), 2.31 (s, 3H, Ar-CH3) ppm.

13


192.49 (-CHO), 167.88 (CO), 164.43, 156.36, 153.47, 152.55, 150.47, 135.20, 133.75, 131.11, 129.34, 127.38, 124.16 (2C), 122.99, 119.77, 115.54 (2C), 114.14, 111.87, 102.97, 36.80 (-CH), 21.39 (Ar-CH3) ppm. Elemental analysis: calcd (%) for C23H16N2O3: C, 74.99; H, 4.38; N, 7.60; Found: C, 74.90; H, 4.37; N, 7.61. ASSOCIATED CONTENT Supporting Information Scanned copies of respective 1H NMR and

13

C NMR spectra for all the synthesized

compounds (4-1 – 4-30) 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.

Conflicts of interest There are no conflicts of interest to declare.

Acknowledgements The authors are thankful to the Science and Engineering Research Board (SERB), Department of Science & Technology (DST), Government of India, New Delhi for providing financial support (Grant No. EMR/2014/001220).IK is grateful to the UGC, New Delhi for awarding him junior research fellowship. The authors are also thankful to DST-FIST Programme, and Department of Chemistry, Visva-Bharati University for infrastructural facilities.

REFERENCES 24


Page 24 of 34

Page 25 of 34 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


(1)

Martins, P.; Jesus, J.; Santos, S.; Raposo, L. R.; Roma-Rodrigues, C.; Baptista, P. V.; Fernandes, A. R. Heterocyclic anticancer compounds: Recent advances and the paradigm shift towards the use of nanomedicine’s tool box. Molecules 2015, 20, 16852-16891. (DOI: 10.3390/molecules200916852)

(2)

Brahmachari, G. Green Synthetic Approaches for Biologically Relevant Heterocycles, Elsevier, Amsterdam, The Netherlands, 2015.

(3)

Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved

pharmaceuticals.

J.

Med.

Chem. 2014, 57,

10257-10274.

(DOI:

10.1021/jm501100b) (4)

Brahmachari, G. Handbook of Pharmaceutical Natural Products, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, Vol. 1 and 2, 2010.

(5)

Patil, P. O.; Bari, S. B.; Firke, S. D.; Deshmikh, P. K.; Donda, S. T.; Patil, D. A. A comprehensive review on synthesis and designing aspects of coumarin derivatives as monoamine oxidase inhibitors for depression and Alzheimer’s disease. Bioorg. Med. Chem. 2013, 21, 2434-2450. (DOI: 10.1016/j.bmc.2013.02.017)

(6)

Amin, K. M.; Eissa, A. A. M.; Abou-Seri, S. M.; Awadallah, F. M.; Hassan,G. S. Synthesis and biological evaluation of novel coumarin–pyrazoline hybrids endowed with phenylsulfonyl moiety as antitumor agents. Eur. J. Med. Chem. 2013, 60, 187198. (DOI: 10.1016/j.ejmech.2012.12.004)

(7)

Sashidhara, K. V.; Avula, S. R.; Sharma, K.; Palnati, G. R.; Bathula, S. R. Discovery of coumarin-monastrol hybrid as potential anti-breast tumor-specific agent. Eur. J. Med. Chem. 2013, 60, 120-127. (DOI: 10.1016/j.ejmech.2012.11.044)

(8)

Bryskier, A.; Klich, M. Antimicrobial Agents; Bryskier, M. D. A., Ed.; ASM Press: Washington, 2005, 816.

(9)

Kharb, R.; Kaur, M.; Sharma, A. K. Imperative advances on antimicrobial activity of coumarin derivatives. Int. J. Pharm. Sci. Rev. Res. 2013, 20, 87-94.

(10)

Najmanová, I.; Dosedêl, M.; Hrdina, R.; Anzenbacher, P.; Filipský, T.; Říha, M.; Mladênka, P. Cardiovascular effects of coumarins besides their antioxidant activity. Curr.

Top.

Med.

Chem.

2015,

10.2174/1568026615666150220112437)

25


15,

830-849.

(DOI:


(11)

Riveiro, M. E.; De Kimpe, N.; Moglioni, A.; Vazquez, R.; Monczor, F.; Shayo, C.; Davio, C. Coumarins: Old compounds with novel promising therapeutic perspectives. Curr. Med. Chem. 2010, 17, 1325-1338. (DOI: 10.2174/092986710790936284)

(12)

Venkatasairam, K.; Gurupadayya, B. M.; Chandan, R. S.; Nagesha, D. K.; Vishwanathan, B. A review on chemical profile of coumarins and their therapeutic role in the treatment of cancer. Curr. Drug Deliv. 2016, 13, 186-201. (DOI: 10.2174/1567201812666150702102800)

(13)

Thakur, A.; Singla, R.; Jaitak, V. Coumarins as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies. Eur. J. Med. Chem. 2015, 101, 476-495. (DOI: 10.1016/j.ejmech.2015.07.010)

(14)

Emami, S.; Dadashpour, S. Current developments of coumarin-based anti-cancer agents in medicinal chemistry. Eur. J. Med. Chem. 2015, 102, 611-630. (DOI: 10.1016/j.ejmech.2015.08.033)

(15)

Kaur, M.; Kohli, S.; Sandhu, S.; Bansal, Y.; Bansal, G. Coumarin: A promising scaffold for anticancer agents. Anticancer Agents Med. Chem. 2015, 15, 1032-1048. (DOI: 10.2174/1871520615666150101125503)

(16)

Keri, R. S.; Sasidhar, B. S.; Nagaraja, B. M.; Santos, M. A. Recent progress in the drug development of coumarin derivatives as potent antituberculosis agents. Eur. J. Med. Chem. 2015, 100, 257-269. (DOI: 10.1016/j.ejmech.2015.06.017)

(17)

Grover, J.; Jachak, S. M. Coumarins as privileged scaffold for anti-inflammatory drug development. RSC Adv. 2015, 5, 38892-38905. (DOI: 10.1039/C5RA05643H)

(18)

Xue, H.; Lu, X.; Zheng, P.; Liu, L.; Han, C.; Hu, J.; Liu, Z.; Ma, T.; Li, Y.; Wang, L.; Chen,Z.; Liu, G. Highly suppressing wild-type HIV-1 and Y181C Mutant HIV-1 strains by 10-chloromethyl-11-demethyl-12-oxo-calanolide A with druggable profile. J. Med. Chem. 2010, 53, 1397-1401. (DOI: 10.1021/jm901653e)

(19)

Anand, P.; Singh, B.; Singh, N. A review on coumarins as acetylcholinesterase inhibitors for Alzheimer’s disease. Bioorg. Med. Chem. 2012, 20, 1175-1180. (DOI: 10.1016/j.bmc.2011.12.042)

(20)

Calcio Gaudino, E.; Tagliapietra, S.; Martina, K.; Palmisano, G.; Cravotto, G. Recent advances and perspectives in the synthesis of bioactive coumarins. RSC Adv. 2016, 6, 46394-46405. (DOI: 10.1039/C6RA07071J)

26


Page 26 of 34

Page 27 of 34 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


(21)

Kumar, D.; Malik, F.; Singh Bedi, P. M.; Jain, S. 2,4-Diarylpyrano[3,2-c]chromen5(4H)-ones as antiproliferativeagents: Design, synthesis and biological evaluation. Chem. Pharm. Bull. 2016, 64, 399-409. (DOI: 10.1248/cpb.c15-00958)

(22)

Jadidi,

K.;

Ghahremanzadeh,

R.;

Bazgir,

A.

Efficient

synthesis

of

spiro[chromeno[2,3-d]pyrimidine-5,3′-indoline]-tetraones by a one-pot and threecomponent reaction. J. Comb. Chem. 2009, 11, 341–344. (DOI: 10.1021/cc800167h) (23)

Sharma, P.; Rane, N.; Gurram, V. K. Synthesis and QSAR studies of pyrimido[4,5d]pyrimidine-2,5-dione derivatives as potential antimicrobial agents. Bioorg.Med. Chem. Lett. 2004, 14, 4185–4190. (DOI: 10.1016/j.bmcl.2004.06.014)

(24) Brahmachari, G.; Nayek, N. A facile synthetic route to biologically relevant substituted

1,4‐naphthoquinonyl‐2‐oxoindolinylpyrimidines

organocatalytic

conditions.

ChemistrySelect

2018,

3,

under

metal‐free

3621−3625.

(DOI:

10.1002/slct.201800462) (25)

Brahmachari, G.; Begam, S.; Nurjamal, K. Sulfamic acid-catalyzed one-pot synthesis of a new series of biologically relevant indole-uracil molecular hybrids in water at room

temperature.

ChemistrySelect

2018,

3,

3400−3405.

(DOI:

10.1002/slct.201800488) (26)

Brahmachari, G.; Nurjamal, K.; Karmakar, I.; Begam, S.; Nayek, N.; Mandal, B. Development of a water-mediated and catalyst-free green protocol for easy access to a huge array of diverse and denselyfunctionalized pyrido[2,3-d:6,5-d′]dipyrimidines via one-pot multicomponent reaction under ambient conditions. ACS Sustainable Chem. Eng. 2017, 5, 9494−9505. (DOI: 10.1021/acssuschemeng.7b02696)

(27)

Brahmachari, G.; Begam, S.; Nurjamal, K. Bismuth nitrate catalyzed one-pot multicomponent synthesis of a novel series of diversely substituted 1,8dioxodecahydroacridines at room temperature. ChemistrySelect 2017, 2, 3311−3316. (DOI: 10.1002/slct.201700265)

(28)

Brahmachari, G. Design for carbon−carbon bond forming reactions under ambient conditions. RSC Adv. 2016, 6, 64676−64725. (DOI: 10.1039/c6ra14399g)

(29)

Banerjee, B.; Brahmachari, G. Room temperature metal-free synthesis of aryl/heteroaryl-substituted bis(6-aminouracil-5-yl)-methanes using sulfamic acid (NH2SO3H) as an efficient and ecofriendly organo-catalyst. Curr. Organocatal. 2016, 3, 125−132. (DOI: 10.2174/2213337202666150812231130) 27



(30)

Page 28 of 34

Brahmachari, G.; Banerjee, B. Ceric ammonium nitrate (CAN): an efficient and ecofriendly catalyst for the one-pot synthesis of alkyl/aryl/heteroaryl-substituted bis(6aminouracil-5-yl)methanes at room temperature. RSC Adv. 2015, 5, 39263−39269. (DOI: 10.1039/c5ra04723d)

(31)

Brahmachari, G. Room temperature one-pot green synthesis of coumarin-3-carboxylic acids in water: a practical method for the large scale synthesis. ACS Sustainable Chem. Eng. 2015, 3, 2350−2358. (DOI: 10.1021/acssuschemeng.5b00826)

(32)

Brahmachari, G.; Choo, C. Y.; Ambure, P.; Roy, K. In vitro evaluation and in silico screening of synthetic acetylcholinesterase inhibitors bearing functionalized piperidine pharmacophores. Bioorg. Med. Chem. 2015, 23, 4567−4575. (DOI: 10.1016/j.bmc.2015.06.005)

(33)

Brahmachari, G.; Das, S. Sodium formate-catalyzed one-pot synthesis of benzopyranopyrimidines and 4-thio-substituted 4H-chromenes via multicomponent reaction at room temperature. J. Heterocyclic Chem. 2015, 52, 653−659. (DOI: 10.1002/jhet.2123)

(34)

Brahmachari, G.; Banerjee, B. Facile and one-pot access of 3,3-bis(indol-3-yl)indolin2-ones and 2,2-bis(indol-3-yl)acenaphthylen-1(2H)-one derivatives via an ecofriendly pseudo-multicomponentreaction at room temperature using sulfamic acid as an organocatalyst. ACS Sustainable Chem. Eng. 2014, 2, 2802−2812. (DOI: 10.1021/sc500575h)

(35)

Brahmachari, G.; Laskar, S. Nano-MgO-catalyzed one-pot synthesis of phosphonate ester functionalized 2-amino-3-cyano-4H-chromene scaffolds at room temperature. Phosphorus,

Sulfur

Silicon

Relat.

Elem.

2014,

189,

873−888.

(DOI:

10.1080/10426507.2014.903484) (36)

Brahmachari, G.; Das, S. L-Proline catalyzed multicomponent one-pot synthesis of gem-diheteroarylmethane derivatives using facile grinding operation under solventfree conditions at room temperature. RSC Adv. 2014, 4, 7380−7388. (DOI: 10.1039/c3ra44568b)

(37)

Brahmachari,

G.;

Banerjee,

B.

A

comparison

between

catalyst-free

and

ZrOCl2·8H2O-catalyzed Strecker reactions for the rapid and solvent-free one-pot synthesis of racemic α-aminonitrile derivatives. Asian J. Org. Chem. 2012, 1, 251−258. (DOI: 10.1002/ajoc.201200055)

28


Page 29 of 34 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


(38)

Brahmachari, G.; Das, S. Bismuth nitrate-catalyzed multicomponent reaction for efficient and one-pot synthesis of densely functionalized piperidine scaffolds at room temperature.

Tetrahedron

Lett.

2012,

53,

1479−1484.

(DOI:

10.1016/j.tetlet.2012.01.042) (39)

Brahmachari, G.; Laskar, S. A very simple and highly efficient procedure for Nformylation of primary and secondary amines at room temperature under solvent-free conditions.

Tetrahedron

Lett.

2010,

51,

2319−2322.

(DOI:

10.1016/j.tetlet.2010.02.119) (40)

Chatel, G. Sonochemistry: New opportunities for green chemistry, World Scientific Publishing Co., Singapore, 2015.

(41)

Schiel, M. A.; Chopa, A. B.; Silbestri, G. F.; Alvarez, M. B.; Lista, A. G.; Domini, C. E. Use of ultrasound in the synthesis of heterocycles of medicinal interest (Chapter 21) in: Green Synthetic Approaches for Biologically Relevant Heterocycles (Ed. Brahmachari, G.), Elsevier, The Netherlands, 2014, pp. 571-601.

(42)

Puri, S.; Kaur, B.; Parmar, A.; Kumar, H. Applications of ultrasound in organic synthesis - a green approach. Curr. Org. Chem. 2013, 17, 1790-1828. (DOI: 10.2174/13852728113179990018)

(43)

Pizzuti, L.; Franco, M. S. F.; Flores, A. F. C.; Quina, F. H.; Pereira, C. M. P. Recent advances in the ultrasound-assisted synthesis of azoles, In: green chemistry – environmentally benign approaches, M. Kidwai (ed) InTech: Rijeka, 2012.

(44)

Baig, R. B. N.; Varma, R. S. Alternative energy input: mechanochemical, microwave and

ultrasound-assisted organic synthesis. Chem. Soc. Rev. 2012, 41, 1559-1584.

(DOI: 10.1039/C1CS15204A) (45)

Brahmachari, G. Design of organic transformations at ambient conditions: Our sincere efforts to the cause of green chemistry practice. Chem. Rec. 2016, 16, 98–123. (DOI: 10.1002/tcr.201500229)

(46)

Yadav, S.; Srivastava, M.; Rai, P.; Singh, J.; Tiwaria, K. P.; Singh, J. Visible light induced, catalyst free, convenient synthesis of chromene nucleus and its derivatives using water–ethanol mixture as a solvent. New J. Chem. 2015, 39, 4556–4561. (DOI: 10.1039/C5NJ00002E)

(47) Frindy, S.; Primo, A.; Lahcini, M.; Bousmina, M.; Garcia, H.; El Kadi, A. Pd embedded in chitosan microspheres as tunable soft-materials for Sonogashira cross29



Page 30 of 34

coupling in water–ethanol mixture. Green Chem. 2015, 17, 1893–1898. (DOI: 10.1039/C4GC02175D) (48) Brahmachari, G.; Laskar, S.; Banerjee, B. Eco-friendly, one-pot multicomponent synthesis of pyran annulated heterocyclic scaffolds at room temperature using ammonium or sodium formate as non-toxic catalyst. J. Heterocyclic Chem. 2014, 51, E303– E308. (DOI: 10.1002/jhet.1974) (49) Jaworski, A. A.; Scheidt, K. A. Emerging roles of in situ generated quinone methides in

metal-free

catalysis.

J.

Org.

Chem.

2016,

81,

10145−10153.

(DOI:

10.1021/acs.joc.6b01367) (50) Luo, J.; Zhang, X.; Zhang, J. Carbazolic porous organic framework as an efficient, metal-free visible-light photocatalyst for organic synthesis. ACS Catal. 2015, 5, 2250−2254. (DOI: 10.1021/acscatal.5b00025) (51) Allais, C.; Grassot, J.-M.; Rodriguez, J.; Constantieux, T. Metal-free multicomponent syntheses

of

pyridines.

Chem.

Rev.

2014,

114,

10829−10868.

(DOI:

10.1021/cr500099b) (52)

Brahmachari, G. Catalyst-free Organic Synthesis, Royal Society of Chemistry: Cambridge, UK, 2018.

(53)

Lupacchini , M.; Mascitti, A.; Giachi, G.; Tonucci, L.; d'Alessandro, N.; Martinez, J.; Colacino, E. Sonochemistry in non-conventional, green solvents or solvent-free reactions. Tetrahedron 2017, 73 , 609-653. (DOI: 10.1016/j.tet.2016.12.014)

(54)

Ma, X.; Keyume, A.; Mamateli, O.; Mengnisa, S.; Reyhangul, R.; Li, W. Facial onepot, three-component synthesis of thiazole compounds by the reactions of aldehyde/ketone, thiosemicarbazide and chlorinated carboxylic ester derivatives. Tetrahedron 2016, 72, 2349–2353. (DOI: 10.1016/j.tet.2016.03.053)

(55)

Kiran, B. M.; Yu-Ting, P.; Wei-Fang, J.; Ding-Yah, Y. Microwave-promoted, catalyst-free, multi-component reaction of proline, aldehyde, 1,3-diketone: One pot synthesis of pyrrolizidines and pyrrolizinones. Tetrahedron 2016, 72, 853–861. (DOI: 10.1016/j.tet.2015.12.056)

(56)

Zhang, X.; Wang, Z.; Xu, K.; Feng, Y.; Zhao, W.; Xu, X.; Yana,Y.; Yi, W. HOTfcatalyzed sustainable one-pot synthesis of benzene and pyridine derivatives under 30


Page 31 of 34 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


solvent-free

conditions.

Green

Chem.

2016,

18,

2313–2316.

(DOI:

10.1039/C5GC02747K) (57)

Khurana, J. M.; Chaudhary, A.; Lumb, A.; Nand, B. An expedient four-component domino protocol for the synthesis of novelbenzo[a]phenazine annulated heterocycles and their photophysical studies. Green Chem. 2012, 14, 2321–2327. (DOI: 10.1039/C2GC35644A)

(58)

Zhu, J.; Bienaymé, H. Eds. Multicomponent Reactions, Wiley-VCH: Weinheim, Germany, 2005.

(59)

Decker, M. (ed.), Design of Hybrid Molecules for Drug Development, Elsevier, Amsterdam, Netherlands, 2017.

(60)

Viegas-Junior, C.; Danuello, A.; Bolzani, V. da S.; Barreiro, E. J.; Fraga, C. A. M. Molecular hybridization: A useful tool in the design of new drug prototypes. Curr. Med. Chem. 2007, 14, 1829-1852. (DOI: 10.2174/092986707781058805)

(61) Brahmachari, G. Design for carbon-carbon bond forming reactions at ambient condition. RSC Adv. 2016, 6, 64676-64725. (DOI: 10.1039/c6ra14399g) (62)

Brahmachari, G.; Banerjee, B. Catalyst-free organic synthesis at room temperature in aqueous and non-aqueous media: an emerging field of green chemistry practice and sustainability.

Curr.

Green

Chem.

2015,

2,

274-305.

(DOI:

10.2174/2213346102666150218195142) (63)

Brahmachari, G. Room Temperature Organic Synthesis, Elsevier: Amsterdam, The Netherlands, 2015.

(64)

Sheldon, R. A. Metrics of green chemistry and sustainability: past, present and future. ACS

Sustainable

Chem.

Eng.

2018,

6,

32–48.

(DOI:

10.1021/acssuschemeng.7b03505) (65)

Abou-Shehada, S.; Mampuys, P.; Maes, B. U. W.; Clarkand, J. H.; Summerton, L.An evaluation of credentials of a multicomponent reaction for the synthesis of isothioureas

through the use of a holistic CHEM21 green metrics toolkit.Green

Chem. 2017, 19, 249- 258. (DOI: 10.1039/C6GC01928E) (66)

Willis, N. J.; Fisher, C. A.; Alder, C. M.; Harsanyi, A.; Shukla, L.; Adams, J. P.; Sandford, G. Sustainable synthesis of enantiopurefluorolactam derivatives by a selective direct fluorination – amidase strategy. Green Chem. 2016, 18, 1313-1318. (DOI: 10.1039/C5GC02209F) 31



(67)

Roschangar, F.; Sheldon, R. A.; Senanayake, C. H. Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration LevelTM concept. Green Chem. 2015, 17, 752-768. (DOI: 10.1039/C4GC01563K)

(68)

Jiménez-González, C.; Constable, D. J. C.; Ponder, C. S. Evaluating the “Greenness” of chemical processes and products in the pharmaceutical industry – a green metrics primer. Chem. Soc. Rev.2012, 41, 1485-1498. (DOI: 10.1039/C1CS15215G)

(69)

Jimenez-Gonzalez, C.; Ponder, C. S.; Broxterman, Q. B.; Manley, J. B. Using the right green yardstick: Why process mass intensity is used in the pharmaceutical industry to drive more sustainable processes. Org. Process Res. Dev. 2011, 15, 912917. (DOI: 10.1021/op200097d)

(70)

Augé, J.A new rationale of reaction metrics for green chemistry.Mathematical expression of the environmental impact factor of chemical processes. Green Chem. 2008, 10, 225-231. (DOI: 10.1039/B711274B)

(71)

Constable, D. J. C.; Curzons, A. D.; Cunningham, V. L. Metrics to ‘green’ chemistry—which are the best? Green Chem. 2002, 4, 521-527. (DOI: 10.1039/B206169B)

(72)

Jiménez-González, C.; Curzons, A. D.; Constable, D. J. C.; Overcash, M. R.; Cunningham, V. L. How do you select the “greenest” technology? Development of guidance for the pharmaceutical industry. Clean Prod. Processes 2001, 3, 35-41. DOI: 10.1007/PL00011310)

(73)

Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, 2000. _________

32


Page 32 of 34

Page 33 of 34 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


GRAPHICAL ABSTRACT

Synopsis Ultrasound when joins hands to organocatalysis: An ultrasound-assisted expedient and green synthetic protocol for functionalized chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6(7H)-ones has been achieved under and sulfamic acid-catalysis at ambient conditions.

Green aspects of the process 1. Synthesis of a new series of biologically interesting polyfunctionalized heterocycles via a newly developed advanced synthetic protocol 2. Use of aqueous ethanol as the green solvent 3. Use of sulfamic acid as a low-cost and eco-friendly solid acid-catalyst, thus a metal-free one-pot synthesis 4. No tedious column chromatography was required for purification of synthesized compounds; simple filtration warrants a practical method. 5. Application of US as a green tool to expedite the reaction rate just at 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 the next cycle 8. Excellent green chemistry credentials with high atom-economy, low-E-factor, and high turnover number

33



Graphic for TOC 72x44mm (300 x 300 DPI)


Page 34 of 34

Ultrasound-Assisted Expedient and Green Synthesis of a New Series

Recommend Documents