Cu(II)–Glucose: Sustainable Catalyst for the Synthesis of

Oct 15, 2018 - ACS eBooks; C&EN Global Enterprise .... Department of Chemistry, Institute of Chemical Technology , Matunga, Mumbai , Maharashtra 40001...
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Cu(II)-Glucose: Sustainable Catalyst for the Synthesis of Quinazolinones in a Bio-Mass Derived Solvent 2MethylTHF and Application for the synthesis of Diproqualone Abhishek V Dubey, and A. Vijay Kumar ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b02940 • Publication Date (Web): 15 Oct 2018 Downloaded from http://pubs.acs.org on October 16, 2018

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Cu(II)-Glucose: Sustainable Catalyst for the Synthesis of Quinazolinones in a Bio-Mass Derived Solvent 2-MethylTHF and Application for the synthesis of Diproqualone Abhishek V. Dubey and A. Vijay Kumar* Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai, Maharashtra400019, India. E-mail of corresponding author: [email protected] ABSTRACT: An efficient method for the synthesis of quinazolinones by a domino cross-coupling reaction of 2-halobenzoic acids and amidines is demonstrated for the first time using copperglucose combination as an inexpensive catalytic system in a bio-mass derived green solvent 2methylTHF. Here glucose plays a dual role, both as a reducing agent generating the low-valent copper ions from cupric precursors and as a chelating agent of the generated low-valent copper species, thereby impeding their deactivation. A wide variety of quinazolinones were synthesized in good to excellent yields. Notably, the activation of less reactive 2-bromo/chlorobenzoic acids by the catalyst not only advocates the efficiency of the developed protocol but also the broad substrate scope. Moreover, the developed methodology was successfully applied to the synthesis of the drug molecule diproqualone. The UV-Vis spectrophotometric titration study of cupric and cuprous salts with glucose showed evidence of glucose playing the role as a ligand, thus may act as a stabilizing agent for the low valent copper species formed in the reaction. The use of inexpensive and air stable cupric salts along with glucose for the synthesis of quinazolinones in a green solvent makes this a benign and sustainable method. ACS Paragon Plus Environment

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KEYWORDS: Bio-derived solvent, Copper-glucose, Quinazolinones, Diproqualone, UV Spectrophotometric study INTRODUCTION: Metal catalysed cross-coupling reactions over the past decades have emerged as a promising tool for the synthesis of various natural products, bioactive moelcules, buidling blocks, etc.1-3 Amongst them, copper mediated cross-coupling reactions have gained more significance when compared to noble metal catalysts due to copper salts abundance, inexpensiveness and immunity towards poisoning agents.4-6 Owing to these features, several copper mediated domino (or) cascade coupling reactions were explored for the synthesis of C-C and C-heteroatom bond formations.7-9 But, a vast majority of these reported methods use expensive/air-sensitive lowvalent copper salts, toxic solvents and demand specialised ligands or additives to achieve significant turnover numbers and efficiency. Such requisites make these methods expensive and of less interesting for use in academia and industry. In this context, from a sustainability point of view, the use of monosaccharides to assist in situ formation of low valent metals for crosscoupling reactions, particularly using cheap copper salts has drawn significant interest due to its several benefits. Monosaccharides10 are eco-friendly, biorenewable and are good cost-effective alternatives to generate in situ low-valent metal species when compared to other reducing agents such as TBAX salts, tetrakis(dimethylamino)ethylene (TDAE), others, etc in metal mediated cross-coupling reactions.11-13 Also monosaccharides stabilize the catalysts through chelation thereby promoting the catalytic cycle and thus preventing the deactivation of the active metal.10 Several groups showcased the use of monosaccharide-metal combination strategy for various reactions such as cross-coupling,14-17 Ullmann reactions,18 multi component reactions,19-22 click reaction23,24 and domino reactions.25 Of all the several monosaccharides that are explored in ACS Paragon Plus Environment

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these applications, glucose is most widely used due to its inexpensiveness, natural availability and ability to reduce many metals very efficiently into colloidal form26. Despite these advantages, there have been very few reports20,25 that demostrate the successful implementation of copper-glucose catalytic system for C-N bond formation which has subsequently drawn our attention to develop a sustainable catalytic system based on copper-glucose for the synthesis of nitrogen

heterocycles

particularly

the

bioactive

nitogen

containing

Quinazolinone

heteroaromatics. Nowadays, solvents derived from renewable raw materials has received significant interest due to exceedingly zero or negligible impact on the environment and health. With the desire of scientific community for turning waste into an asset, intensive research activity over biomass conversion have developed several new platform chemicals, such as γ-valerolactone (GVL), lactic acid, ethyl lactate, 2-methyltetrahydrofuran and limonene, which could well replace currently used organic solvents.27-30 In particular, 2-methyltetrahydrofuran (2-MeTHF)31 is a promising alternative biobased solvent efficiently produced from renewable lignocellulosic biomass (from furfural or levulinic acid) and can be abiotically degraded by sunlight and air via oxidation and ring-opening reactions. The physical and chemical properties of 2-MeTHF i.e. polarity, boiling point, good stability to acidic and basic environments and low water miscibility make it appealing for various synthetic organic transformations. Quinazolinones are one of the most prevalent heterocycles that are diversely found in many natural products, drugs and biologically important molecules.32-38 As shown in Fig. 1, several of these compounds are also known to be cytotoxic, anti-fungal, hypnotic, anti-endotoxic, etc. inhibit insulin secretion and smooth muscle contractile activity by attacking KATP channel activity. Previously reported syntheses of these derivatives rely on precursors such as ortho-amino or ortho-nitro benzoic acids. Owing to the importance of quinazolinones, various synthetic efforts have been made to prepare them from a variety of starting materials.39-43 ACS Paragon Plus Environment

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O

O

O

N

NH

N N

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OH

N

OH

(+)-Vasicinone

O NH

O N

N

A natural firefly luciferase inhibitor

N

CH3 N CH3

NHCH3

N CH3

Glycomerine

Glycorine O

O

NH

N

CHO

N

N

N

HN

Luotonin A O N

HN

Vasnetine R = -COOCH3

Chrysogine

O

R

N

Ph

Bouchardatine O

O N

N

N

(E)-Bogorin (Cytotoxic & anti-fungal)

N CH3

Methaqualone (Sedative)

N

COOH

3-(2-Carboxyphenyl)-4(3H)quinazolinone(Anti-endotoxic)

Figure 1. Biologically Important Compounds and Natural Products Containing Quinazolinone Ring

However, the feasibility of these methods are limited due to constraints such as substrate availability. A major breakthrough reported by Fu et al. desribes a CuI-catalysed route for the synthesis of 2-alkyl and 2-aryl substituted quinazolinones from readily available orthohalobenzoic acids via a tandem reaction.44 Although the approach was highly efficient and ligand free, the use of expensive and air sensitive CuI salt, hazardous/toxic solvents to achieve high yields can be deemed as a non-sustainable approach. Additionally, several other methods are reported using various metals such as Pd,45 Cu,46-56 Ir,57,58 Au,59 Fe60-62, Mn63 and non-metal64-71 ACS Paragon Plus Environment

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using precursors such as 2-halobenzoic acids, 2-nitrobenzonitrile, 2-aminobenzamide, 2iodobenzamide, 2-iodobenzonitrile and 2-iodoaniline. Moreover, most of these procedures employ expensive ligands, harmful solvents, high temperature reaction conditions, metal/nonmetal oxidant, limited substrate study and need tedious procedures to prepare catalysts. Scheme 1. depicts all recent developments for the synthesis of quinazolinones using various metals and substrate. Few of these methods use expensive metals, harsh reaction conditions and environmentally non-benign solvents. Interestingly, literature survey showed that the the metalmonosaccharide approach has not been explored for the synthesis of quinazolinones. Therefore with a view to amalgamate such ideas and considering the importance of these scaffolds and motifs, in continuation to our sustainable method development program,72-77 we intended to use the combination of glucose and cupric salts to generate in situ low valent copper species as sustainable catalyst in a green solvent for benign synthesis of quinazolinones. The E-factor for different catalytic methods for the synthesis of quinazolinones including ours is shown in shown in scheme 1 for comparison. NH2

R1

R '-NH2

I

Pd/-Cyclodextrin, TMOF

O 2N

Au/TiO2

CO, TEA, GVL/ACN, 125oC synthMW reactor

R2

OH

o

Ref. 59 E-factor = 2.96

Ref. 45 E-factor = 1.79 O

O

OH

R1

NH2 HCl

HN R

X

2

KOH, DMSO, 120oC, N2

R1 N

H 2N

1. [Cp*IrCl2]2, p-xylene, 70oC N

NH

2.

R2

R1

OH

CuO, POCl3, R2CN, rt-80oC

o

PhCHO, 110 C

NH2 Ref. 46 E-factor = 40.78

NC Ref. 58 E-factor = 9.19 O

-MnO2-150, TBHP Cu(OAc)2.H2O Glucose 2-MeTHF, rt-80oC, N2

R1

OH

Ref. 70 E-factor = 12.09 O

R1

NC

H2O, 130 C

o

chlorobenzene, 80 C This work

R2

OH

H 2N

R1

H 2N Ref. 63 E-factor = 24.92

E-factor = 18.19

O OH X

NH2 HCl

HN R2

Scheme 1. Different Catalytic Approach for the synthesis of Quinazolinones

EXPERIMENTAL SECTION: All reagents and starting materials were obtained from commercial sources and were used without additional purification. Thin Layer Chromatography (TLC) was performed on silica

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(Silica Gel 60 F254) pre-coated aluminum plates and the products were visualized by UV lamp (PHILIPS TUV 8W lamp) and I2 stain. UV-visible study performed on Shimadzu UV-1800 spectrophotometer at room temperature Quartz cuvettes with a 1 cm path length and 2 mL volume were used for all measurements. The 1H and

13C

NMR was recorded in CDCl3 using

residual solvent peak as a reference on an Avance III and Bruker NMR spectrophotometer at 400 MHz and 101 MHz respectively. Most of the compounds require only flash column chromatography, as they formed no side products. A short pad of silica with pure ethyl acetate in many cases afforded the analytically pure product. General reaction procedure for quinazolinone synthesis To a solution of copper acetate (20 mg, 10 mol %) in 2-MeTHF (3 mL), glucose (54 mg) was added, to this 2-iodobenzoic acid (1 mmol), amidine hydrochloride (1.1 mmol) and cesium carbonate (2.5 mmol) were added. The reaction mixture was vigorously stirred under nitrogen atmosphere at room temperature till complete conversion of the starting material (as monitored by TLC). After the reaction was completed, the mixture was passed through the celite bed, and the organic layer was evaporated under reduced pressure. The product was isolated by flash column chromatography on silica which was further completely characterized. General reaction procedure for UV study Filtrate of 0.0119 M solution of Cu(OAc)2.H2O and glucose were used for UV study. RESULTS AND DISCUSSION: Initially, reaction optimisation study was carried out with 2-iodobenzoic acid and benzamidine hydrochloride as model substrates for various reaction parameters like catalyst, ligand, base, temperature, time, and solvent. The results are summarized in Table 1. The coupling product 2-phenylquinazolin-4(3H)-one (3a) was obtained in 91% yields with Cu(OAc)2.H2O (0.1 mmol) metal salt, Cs2CO3 (2.5 equiv.) as base and 2-Methyl THF as the

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Table 1. Screening of different bases, solvents and copper catalysts for the reaction of 2iodobenzoic acid with benzamidine hydrochloride under reaction condition.a O OH I 1a

NH2 HCl HN

Ph

O

glucose

NH

base, solvent, rt, 24 h

N 3a

2a

Ph

Entry

Catalyst

Base

Solvent

Yield [%]b

1

Cu(OAc)2.H2O

Cs2CO3

2-MeTHF

91

2

Cu(OAc)2.H2O

Na2CO3

2-MeTHF

41

3

Cu(OAc)2.H2O

K2CO3

2-MeTHF

63

4

Cu(OAc)2.H2O

Na3PO4

2-MeTHF

55

5

Cu(OAc)2.H2O

K3PO4

2-MeTHF

59

6

Cu(OAc)2.H2O

KF

2-MeTHF

16

7

Cu(OAc)2.H2O

NEt3

2-MeTHF

27

8

Cu(OAc)2.H2O

KOtBu

2-MeTHF

58

9

Cu(OAc)2.H2O

KOH

2-MeTHF

52

10

CuCl2.H2O

Cs2CO3

2-MeTHF

47

11

CuSO4.5H2O

Cs2CO3

2-MeTHF

24

12

CuBr

Cs2CO3

2-MeTHF

62

13

Cu(OAc)2.H2O

Cs2CO3

DMSO

71

14

Cu(OAc)2.H2O

Cs2CO3

Dioxane

12

15

Cu(OAc)2.H2O

Cs2CO3

Toluene

Trace

16

Cu(OAc)2.H2O

Cs2CO3

H 2O

Trace

17

Cu(OAc)2.H2O

Cs2CO3

MeCN

69

18

Cu(OAc)2.H2O

Cs2CO3

DMF

91

19

Cu(OAc)2.H2O

Cs2CO3

i-PrOH

63

20

Cu(OAc)2.H2O

Cs2CO3

2-MeTHF

73c, 91d

21

Cu(OAc)2.H2O

Cs2CO3

2-MeTHF

37e, 76f

22

--

Cs2CO3

2-MeTHF

Trace

23

Cu(OAc)2.H2O

Cs2CO3

2-MeTHF

21g

aReaction

conditions: 2-iodobenzoic acid (1 mmol), benzamidine hydrochloride (1.1 mmol), catalyst (0.1 mmol), glucose (0.3 mmol), base (2.5 equiv.) and solvent (3 mL) at room temperature (25 oC) under a nitrogen atmosphere. bIsolated yield. cbase (2 equiv.) dbase (3 equiv.). eNo glucose. fglucose (0.2 mmol). gunder air atmosphere. ACS Paragon Plus Environment

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solvent under a nitrogen atmosphere at room temperature over 24 h (Table 1, entry 1). Performing the reaction using various inorganic and organic bases hindered the reaction progress, also stronger bases such as KOH, KOtBu decreased the yield (Table 1, entries 8 and 9). Likewise, poor yields were observed when bases such as KF, Et3N were used (Table 1, entries 6 and 7). Whereas the use of carbonates and phosphate bases afforded moderate product yields (Table 1, entries 2-5). Further, screening of copper(I) and copper(II) salts as catalysts was less promising as neither of them gave better results. The copper(II) salts viz. CuSO4 and CuCl2.H2O showed low activity when compared with Cu(OAc)2.H2O, however we were able to get moderate yields in case of Cu(I) salts (Table 1, entries 10-12). Considering reaction media, when the reactions were performed in common solvents such as toluene, H2O and dioxane no product formation or poor conversions were seen (Table 1, entries 14-16). Use of other solvents like DMSO, MeCN and i-PrOH were found to be encouraging but the reactions failed to go for completion (Table 1, entries 13, 17 and 19). Moreover, excellent product yield was obtained with DMF as solvent (Table 1, entry 18), however due to its hazard index, it was least preferred as the solvent of choice. In continuation, we also tested the effect of quantity of base; the influence of amount of base on the product yields was studied in the range of 2.0 to 3 equivalents (Table 1, entries 1, 20 and 21), of which 2.5 equivalents afforded the best product yield ((Table 1, entry 1). Drastic reduction of product yield was observed in the absence of glucose; low yields were observed when the amount of glucose was less than 0.3 mmol (Table 1, entry 21). Only trace amounts of the desired product was obtained when the experiment was performed in the absence of both copper (Table 1, entry 22) and nitrogen atmosphere (Table 1, entry 23). This strongly proved that copper and nitrogen atmosphere are essential to carry out this transformation. With these promising results in hand, we proceeded to investigate the scope of the crosscoupling domino reaction under the optimized conditions with a wide range of C-3, C-5

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Table 2. Copper-catalyzed synthesis of quinazolinone derivatives with different 2-iodobenzoic acida O

Cu(OAc)2.H2O (10 mol%) NH2 HCl D-Glucose (30 mol%)

OH

R

HN

I

R'

O NH

O2N

3f, 88% O

NH N

3g, 81%

3h, 83%

O

N

N

3j, 83%

3k, 88%

N

Ph

MeO N

O2N

O

NH

NH N

3q, 87%

3p, 81% O

F

O O 2N

NH

NH

N

N

3r, 85%

N

3s, 86% O

Ph

3m, 89%

N

O NH

NH

Ph

3l, 87%

3o, 87%

F

O

N

N

3n, 83%

3i, 89%

O NH

Ph

N

NH

O NH

NH

O

NH

O

O

F

N

F

NH

3e, 86%

O NH

N

O 2N

3d, 84%

O NH

N

N

3c, 87%

O

NH

NH

N

MeO

O

O NH

N

3b, 85%

NH

R

N R' Cs2CO3 (2.5 eq.), 2-MeTHF rt , N2, 24 h (3b-3v) Yieldb (%)

O

NH2

O

C(CH3)3

3t, 82% O

NH N

3u, 89%

C(CH3)3

H3CO

NH N

C(CH3)3

3v, 91%

aReaction

conditions: 2-iodobenzoic acid derivatives (1 mmol), amidine hydrochloride (1.1 mmol), catalyst (0.1 mmol), glucose (0.3 mmol), base (2.5 equiv.) and solvent (3 mL) at room temperature (25 oC) under a nitrogen atmosphere. bIsolated yield.

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substituted 2-halobenzoic acid and a variety of amidine substrates. We were pleased to observe that the cascade reactions proceeded smoothly at room temperature with various electronwithdrawing and electron-donating 2-iodobenzoic acids, to afford the corresponding quinazolinone derivatives in good to excellent yields (Table 2, entries 3b-3v). It is noteworthy to mention that the quinazolinone scaffolds were formed selectively in good to excellent yields with substituted 2-iodobenzoic acid bearing a halogen atom at C-5 position without any side product formation. These substituted quinazolinones have been utilized for the synthesis of Schizocommunin derivatives78 which opens the scope for further modification of such quinazolinone moieties. Moreover, electron-donating group at 2-iodobenzoic acids were found to give slightly higher yields when compared to withdrawing counterpart. The effect of the substituents at amidines was found to give slight variation on product yields. However, a minor decrease in reactivity is observed with C-5 nitro and C-3 methyl substituents at 2-iodobenzoic acid (Table 2, entry 3g).

Table 3. Copper-catalyzed synthesis of quinazolinone derivatives with 2-bromobenzoic acid.a O OH Br

Cu(OAc)2.H2O (10 mol%) NH2 HCl D-Glucose (30 mol%) HN Ph Cs CO (2.5 eq.), 2-MeTHF 2

3

60 O

O NH N

Ph

3a, 81% and 27%c

oC

, N2, 24 h

O NH

O NH N Ph (3a-3e) Yieldb(%)

NH

N

N

3b, 74%

NH2

O

O

3c, 79%

NH

NH N 3d, 78%

N 3e, 76%

aReaction

conditions: 2-bromobenzoic acid (1 mmol), amidine hydrochloride (1.1 mmol), catalyst (0.1 mmol), glucose (0.3 mmol), base (2.5 equiv.) and solvent (3 mL) at 60 oC under a nitrogen atmosphere. bIsolated yield.

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Table 4. Copper-catalyzed synthesis of quinazolinone derivatives with 2-chlorobenzoic acid.a O OH Cl

HN

Ph

Cs2CO3 (2.5 eq.), 2-MeTHF 80 oC , N2, 24 h

O

O

Ph

O NH

NH N

O

Cu(OAc)2.H2O (10 mol%) NH2 HCl D-Glucose (30 mol%)

NH N Ph (3a-3e) Yieldb (%)

NH

N

O

O

N

NH

NH N

N

NH2

3a, 62%

3b, 63%

3c, 64%

3d, 58%

3e, 61%

aReaction

conditions: 2-chlorobenzoic acid (1 mmol), amidine hydrochloride (1.1 mmol), catalyst (0.1 mmol), glucose (0.3 mmol), base (2.5 equiv.) and solvent (3 mL) at 80 oC under a nitrogen atmosphere. bIsolated yield.

The reactions of 2-bromobenzoic acid and amidine provided lower yields of target product at room temperature. However good yields were observed when temperature was raised to 60 oC (Table 3, entry 3a). Aryl chlorides which are relatively unreactive substrates in coupling reactions were also found to give the corresponding quinazolinone products in moderate yields at slightly higher temperature compared to aryl bromides (Table 4, 64−58%, 3a-3e). In general, the reactivity of 2-halobenzoic acids towards this cross-coupling domino reaction is found to be in order of aryl iodide > aryl bromide > aryl chloride with respect to yields (Table 1, 2, and 4, 91−58%, 3a-3v). Further next, to understand the reaction mechanism and gain insights for the formation of quinazolinones, we performed a few control experiments. To examine the role of carboxylic group in product formation, iodobenzene was reacted with amidine under the standard reaction conditions. No Ullmann product was obtained, wherein the reactants remained unconsumed, which clearly indicated that the ortho- carboxylic group substitution has a profound effect on the formation of products, thus suggesting a possible pre-organized copper carboxylate species. On the other hand, addition of radical scavengers such as TEMPO (2, 2, 6, 6ACS Paragon Plus Environment

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tetramethylpiperidinooxy) did not influence the reaction, which verified that the reaction does not proceed through the formation of short lived radicals and hence eliminates the possibility of a radical pathway mechanism. (Scheme 2, A & B). In order to find out whether the amide formation or cross-coupling step is first, we performed two control experiments wherein Nbenzoylamidine derivative of 2-iodobenzoic acid was synthesized,79 characterized and subjected to cyclization conditions (copper, glucose and Cs2CO3, 2-MeTHF) (Scheme 2, C). Unfortunately, the reaction did not proceed to afford the expected quinazolinone. This proved that the crosscoupling step is the first step in the cascade process. Also recalling the results of Scheme 2. A, it suggests that the coordination of the carboxylic acid is required for the product formation. NH HCl

A) H2N

I

COOH

Ph

NH HCl

B)

H2N

I

Ph

Cu(OAc)2.H2O D-Glucose

X

Cs2CO3, 2-MeTHF, 24h, rt TEMPO Cu(OAc)2.H2O D-Glucose Cs2CO3, 2-MeTHF, 24h, rt

NH N H

Ph

No Ullmann product O NH N

Ph

91% O C)

Cu(OAc)2.H2O D-Glucose

NH N H

Ph

I

O

X

Cs2CO3, 2-MeTHF, 24h, rt

NH N

Ph

No product D)

COOH

NH HCl H2N

Ph

NH HCl I

O NH

X

Cs2CO3, 2-MeTHF, 24h, rt

HN

Ph

No product

COOH E)

Cu(OAc)2.H2O D-Glucose

H2N

Ph

Cu(OAc)2.H2O D-Glucose

X

No reaction

Cs2CO3, 2-MeTHF, 24h, rt

Scheme 2. Mechanistic study for synthesis of quinazolinone in different reaction conditions In another control experiment, we carried out the reaction of benzoic acid with benzamidine salt under our reaction conditions (copper, glucose and Cs2CO3, 2-MeTHF), no

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amide bond formation took place. This strongly supported that copper may not be catalyzing the amide bond forming step (Scheme 2, D). Also the reaction of 3-iodobenzoic acid failed to form the product (Scheme 2, E). Further next, in order to understand the synergism between copper and glucose

80,81

in

terms of catalytic activity, UV-Vis spectrophotometric titration studies of copper (II) acetate with glucose were carried out. It has been found that, copper (II) salt solution shows maximum absorbance at 680nm, however the absorption decreased with the incremental addition of glucose (Scheme 3).

Scheme 3. UV-Vis spectrophotometric titration of copper (II) acetate with glucose

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With the increase in addition of glucose equivalents, the concentration of copper (II) ions proportionally decreases, at a certain point (beyond 3equiv. of glucose) the peaks absorption intensity becomes constant. Besides this, we performed another UV-Vis study of copper (I) acetate [commercially procured] with glucose. Interestingly, copper (I) acetate showed a strong absorption band at 700nm which upon addition of glucose (1 equivalent and 3 equivalents) has resulted in significant reduction of intensity (Figure S1, Supporting information). Both, these studies strongly suggest that the reduction of intensity in UV-Vis titration may be due to ligand exchange process around copper. Three equivalents of glucose might be completely replacing the acetate ligands. These results strongly support that glucose acts as ligand in the reaction. Additionally, we recorded the UV-Vis absorption for the filtered reaction mixture with and without glucose. A decrease in intensity of peak was observed in the case of glucose (Scheme 4), suggesting glucose might be replacing the acetate ligands around copper. In order to gain further insights of reaction, we performed the mass spectrometric analysis of the reaction mixture after complete conversion of the substrates. The analysis showed peaks corresponding to gluconic acid (M+Na, 219m/z) and also the gluconic acid dimer (392 m/z) (Figure S2-S4, Supporting information). From this analysis it can be concluded that glucose gets oxidized to gluconic acid in the reaction. The mass spectra analysis of native glucose was also carried out, which showed no contaminations of gluconic acid thus suggesting that glucose converts to gluconic acid in the reaction (Figure S5, Supporting information). Based on all these above results, a plausible mechanistic pathway82 is proposed (Scheme 5). Intially, low valent copper species formation can take place as glucose is a reducing sugar (Fehling‘s reaction). The low valent copper can subsequently undergo oxidative addition along with ligation by the nucleophile (step I - II) followed by reductive elimination and cyclization leading to formation of the quinazolinone along with the regeneration of low-valent copper which goes into the next catalytic cycle (step III - IV). Even though we failed to see reduced copper species in the XPS (Figure 2 & 3) of ACS Paragon Plus Environment

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Scheme 4. UV-Vis spectrum of reaction mixture, with and without glucose.

Cu(OAc)2.H2O + Glucose

Step II Step I

O L Cu (I) or L Cu (0)

OH

R1 X

NH2

HN

L Cu O

Cs2CO3

R

2

O

R1

X

O O

R1

L Cu X NH2

HN O

O NH

R1 N

R

NH2

N H2 O

Step IV

R

OH

R1 2

CuX

2

R

2

Step III

L = Gucose / Gluconic acid

Scheme 5. Plausible mechanistic pathway for copper-glucose catalysed quinazolinones synthesis

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Figure 2. XPS analysis of copper reaction mixture

Figure 3. XPS analysis of copper reaction mixture

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the reaction mixture (filtered residue after complete conversion of the reactants). However, chances of in situ formed species cannot be ruled out. We beleive that such particles/species/clusters if at all formed might get destroyed by the ammonia remnats emanating from the amidine substrates used in the reaction. It is also known that none of the copper oxides survive in ammonia solutions.83, 84 Further, to explore the utility of this novel sustainable catalytic system, the synthesis of bioactive compound (or) drug molecule was also investigated. Literature survey revealed that (±) Diproqualone,85 an analogue of methaqualone is the only drug molecule that is still in use worldwide not only because of its useful sedative and anxiolytic actions but also due to its unique anti-inflammatory and analgesic properties which is not commonly observed in other drugs of this class. For synthesis of this, we tried one-pot reaction of 2-iodobenzoic acid and acetamidine hydrochloride under the developed reaction conditions. After completion of the reaction, subsequently we added 3-chloro-1,2-propanediol in the same flask under reflux conditions to get the N-arylated molecule. The yield for the two consecutive steps is found to be 78% (Scheme 6). Finally, we succeeded in applying the developed methodology for the synthesis of (±)-Diproqualone and this strategy can be a promising platform for the synthesis of many such drug molecules in a benign way.

O OH I

2- Iodobenzoic acid 1 mmol

NH NH2 .HCl

Acetamidine hydrochloride 1.1 mmol

Cu(OAc)2.H2O (10 mol%) D-Glucose (30 mol%) 1) Cs2CO3(2.5 eq.), 2-MeTHF rt, N2 , 24 h 2)

N N

OH Cl

O

OH

3-Chloro-1,2-propane diol ( 2 equiv.) reflux

OH OH

3w, 78%

(±) Diproqualone

Scheme 6. One-pot synthesis of Diproqualone by using copper-glucose catalysed quinazolinone reaction as key step.

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CONCLUSION: In conclusion, we have developed an inexpensive and environmentally benign methodology

for

the

synthesis

of

quinazolinones

from

readily

available

2-

iodo/bromo/chlorobenzoic acids with various amidines using Cu(OAc)2.H2O-glucose as catalytic system in green solvent 2-methylTHF. This is the first report of direct usage of readily available glucose with readily available inexpensive transition metal such as copper for the synthesis of quinazolinones using various halides and amidine substrates to afford the desired products in moderate to excellent yields. The mild reaction conditions, affordable catalytic system and use of bio-derived solvent, 2-methylTHF makes this a sustainable protocol, could further open up new scope for such domino synthetic organic transformations. Moreover, a UV-Vis study proved that glucose plays a significant role as a ligand and stabilizing agent for the the low valent copper species formed in the reaction. Furthermore, the developed methodology was utilized for the synthesis of (±)-Diproqualone drug molecule.

Associated content Supporting Information 1H-NMR

& 13C-NMR; UV-VIS, XPS, Mass spectrometry data.

Author Information Corresponding Author Tel.: +91 22 33612614. E-mail: [email protected] ORCID A. Vijay Kumar: 0000-0001-9753-0590 Notes The authors declare no competing financial interest.

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ACKNOWLEDGEMENTS: AVD is grateful to University Grant Commission (UGC) for the research fellowship. AVK is thankful to DST, Govt. of India, for the research funds, DST-SERB (YSS/2015/002064). Department of Pharmaceutical Sciences and Technology, ICT, for NMR analysis. REFERENCES: 1. Meijere, A. D.; Brase, S.; Oestreich M., Metal-Catalyzed Cross-Coupling Reactions and More, Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2014, 1–1511.

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TOC:

Cu-Glucose O

O NH

OH

R X

2- Halobenzoic acids X = I, Br, Cl

R'

Amidines R' = alkyl or aryl

NH

R

NH2 HCl

N O Solvent

CH3

R'

Quinazolinones 33 examples, 91-58%

rt to 80oC O

    

Benign protocol Bio-derived solvent Mild conditions Sustainable catalyst Broad substrate scope

N N

OH OH

(±) Diproqualone

Copper (II)-glucose as a sustainable catalyst for the efficient synthesis of quinazolinones is developed in a biomass derived solvent 2-methylTHF and the methodology was utilized for the synthesis of Diproqualone.

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