Metal-Free Greener Syntheses of Pyrimidine Derivatives Using a

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Metal-free greener syntheses of pyrimidine derivatives using highly efficient and reusable graphite oxide carbocatalyst under solvent-free reaction condition Binoyargha Dam, Ramen Jamatia, Ajay Gupta, and Amarta Kumar Pal ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b02626 • Publication Date (Web): 17 Oct 2017 Downloaded from http://pubs.acs.org on October 21, 2017

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ACS Sustainable Chemistry & Engineering

Metal-free greener syntheses of pyrimidine derivatives using highly efficient and reusable graphite oxide carbocatalyst under solvent-free reaction condition Binoyargha Dam,a Ramen Jamatia,a Ajay Gupta,a and Amarta Kumar Pala* a

Department of Chemistry, Centre for Advanced Studies, North-Eastern Hill University, Umshing, Mawkynroh

Shillong-793022, India, E-mail: [email protected], [email protected]

Abstract: Graphite oxide, a green metal-free carbocatalyst has been successfully exploited for the library synthesis of biologically active pyrimidine derivatives. Reaction was carried out under solvent-free reaction conditions (SFRC) thereby reducing the application of hazardous chemicals and solvents. Present catalytic system eliminates the risk of metal contamination in product which is viable for pharmaceutical industries, and showed better catalytic activity under sustainable conditions compared to other classical catalytic systems. Catalyst being heterogeneous in nature can be easily recycled and reused up to nine consecutive runs without much decrease in catalytic activities thereby increasing sustainability of the procedure. Diversity in the formation of pyrimidine moieties has been exhibited with the tolerance of a large number of functional groups establishing the generality of this reaction. Few other cutting edge advantages of the present one-pot multi-component methodology are high atom economy, low catalyst loading, milder reaction condition, higher yield of the desired product, simple work up procedure, easy handling of the catalyst etc. The present methodology showed good results in gram scale condition thereby indicating its applicability in academic as well as industries in near future. Key words: Metal-free carbocatalyst, graphite oxide, solvent-free reaction condition, pyrimidine, recyclable catalyst, multi-component reaction.

ACS Paragon Plus Environment


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Introduction:

Sustainable chemistry commonly known as ‘Green chemistry’ is a philosophy of modern day chemical engineering and research which deals with the development of environment friendly procedures1 for synthesizing biologically significant compounds. Recently field of catalysis has emerged as heart of many chemical protocols because it lowers the activation energy and makes the reaction feasible. Application of clean and reusable catalytic material is one of the principles of green chemistry.2-5 So, in this connection search for sustainable, environmentally benign and efficiently reusable catalytic system has become vital. Owing to high natural abundance of carbon, development of carbon materials as green catalysts is one of the hot topics in research around the world.6 Significance of graphene (an allotrope of carbon) in engineering, nanotechnology and electrochemistry has been documented by the Nobel prize of 2010.7,8 Graphene because of its astonishing thermal, optical, mechanical, electronic properties, large surface area and

bio-compatibility has

emerged as a new class of heterogeneous catalyst.9-17 Till date, graphene and related carbon materials has been used mainly as a support for catalytically active transition metals.18-21 But, after Bielawski’s application of pristine graphite oxide in the oxidation of alcohols to corresponding carbonyl compounds, it gained worldwide attention and was being applied in many organic reaction involving C-C22 and C-heteroatom bond formation,23 alkyne hydration,24 thiol oxidation,25 oxidative coupling of amines to imines 26 etc. High reactivity of graphite oxide is due to the presence of various functional groups like hydroxyl (-OH), epoxy (-O-), and carboxyl (-COOH) on its surface,27 which prompted us to apply this carbocatalyst in multi-component reaction, which intern very efficiently drove the reaction towards completion.


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Because of growing concerns on environment, various research groups recently are focussing on sustainable synthesis.28-39 Therefore application of nanomaterials as recyclable catalysts in these sustainable synthesis is much demanding.30-35 Multi-component reactions (MCRs) has been acknowledged as an essential tool for the greener synthesis of biologically important complex molecules by eliminating the isolation of intermediates and reducing the number of discrete chemical steps and waste products.36-41 Pyrimidine and its derivatives are an important class of heterocyclic compound which exist in the core of many biologically active natural products. They possess several pharmaceutical activities like anticancer,42 antibacterial,43 antileishmanial,44 analgesic,45 antidiabetic,46 antiallergic,47 antifungal,48 antipyretic,49 herbicidal,50 calcium channel blocker,51 central nervous system depressant52 etc. Structures of some biologically active molecules containing pyrimidine blocks are shown in Fig. 1. Afloqualone, epirizole, lamivudine and minoxidil were found to exhibit antiinflammatory,53 analgesic,53 anti-HIV54 and antihypertensive55 properties respectively. Because of these properties various synthetic methodologies have been developed for pyrimidine analogues over the years.56-60 Each methods have their own advantages but many of these procedures lack their application under sustainable conditions due to the use of i) corrosive catalysts like base,61 sulfamic acid,62 p-toluenesulfonic acid monohydrate,63 boric acid,64 silica sulphuric acid,65 ii) hygroscopic, difficult to handle, costly and unrecyclable catalysts like AlCl3,66 FeF3,67 [bmim]BF4,68 molecular iodine,69 guanidine chloride,70 iii) heterogeneous metal catalyst like nickel nanoparticles,71 Nano-WO3-supported sulfonic acid,72 copper nanoparticles etc.73 because of which problems like quandary of waste disposal and contamination of metals in desired products are arising thereby necessitating of tedious work up for the removal of metal impurities from the final product. Moreover most of the above mentioned catalytic systems required application of toxic solvents, but it is always recommended to develop a process in absence of any solvents, which is an important view



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point of green chemistry.74 Recently, T. Raj and group57 synthesized the present compound by ball milling technique but limited substrate variation (only alkylacetoacetates as

β−dicarbonyl compounds) was explored thereby limiting their methodology. Again P. K. Sahu and group reported synthesis of the said compound by using chitosan,75 but for homogenizing the catalyst with the reaction mixture as well as to increase its efficiency they used 2 % acetic acid solution which is not environmentally benign, moreover reaction was not extended to benzoimidazole and thiazole derivatives, neither the reaction was compatible with aliphatic, heteroaromatic aldehydes nor with aldehydes possessing multiple carbonyl groups. F

H N

O N

H2N

O N

S

N N

O

(Afloqualone) anti-inflammatory

HO

N

(Epirizole) analgesics

N O

NH2 N

O

(Lamivudine) anti-HIV

N N H2N

N

NH2

(Minoxidel) antihypertensive Fig. 1: Structures of some biologically active pyrimidine molecules The research work described herein address the above mentioned issues and developed an eco-friendly and sustainable protocol by using metal free recyclable graphite oxide carbocatalyst under solvent-free reaction condition. Few other advantages of this current methodology are shorter reaction time, higher yield of the desired product, easy handling and excellent reusability of the catalyst, and high substrate variation etc.


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Results and discussion: Preparation and characterization of Catalyst: In our present attempt to develop a metal-free greener synthesis of fused pyrimidine derivatives, we choose graphite oxide as a heterogenous catalyst. Graphite oxide was prepared from graphite powder according to modified Hummer’s method (Scheme 1).76,77 Prepared graphite oxide was then characterized by several spectral techniques like Fourier Transform –Infrared (FT-IR) spectroscopy, Scanning electron microscopy (SEM), Electron dispersive X-ray (EDX) spectroscopy, Transmission electron microscopy (TEM), Powder XRD, Raman spectroscopy, Thermogravimetric analysis (TGA) and X-Ray photoelectron spectroscopy (XPS).

OH

COOH COOH COOH OH COOH

O O HOOC

O

O HOOC HOOC COOH

OH

HOOC COOH COOH OH COOH

O O Oxidation

HOOC

O

O HOOC HOOC OH

HOOC COOH COOH COOH OH COOH

O O HOOC

O

O HOOC HOOC HOOC graphite oxide

graphite powder Scheme 1: Synthesis of graphite oxide

Firstly to determine functional groups present in the synthesized catalyst we carried out an FT-IR analysis (Fig. 2). In FT-IR spectra the appearance of peaks at around 3386, 1732, 1047 cm-1 indicated presence of hydroxyl, carboxyl and epoxy functional groups respectively.78



Then in order to get a fair idea regarding structure and shape of graphite oxide, SEM images were taken. Fig. 3A shows SEM image of graphite oxide which indicates that it possess a sheet like structure. Following that an elemental analyses of synthesized graphite oxide was performed by EDX and it showed presence of carbon and oxygen (Fig. 3B). Weight % and atomic % of carbon and oxygen were found to be 27.25, 72.75 % and 33.29, 66.71 % respectively. To further gain information regarding structure of catalyst we took HR-TEM images of graphite oxide and it showed presence of distinct multi-layered graphite oxide sheet (Fig. 3C).

Selected area electron diffraction (SAED) pattern of sample shows

characteristic hexagonal pattern for graphite oxide (Fig. 3D).77

40

35

% Transmitance

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30

596 1732 25

1626 1047 20

1107 15

3386 10 3000

2000

1000 -1

Wave number (cm )

Fig. 2: FT-IR spectra of graphite oxide (A)

(C)

(B)

(D)

Fig. 3: (A) SEM image of graphite oxide (B) EDX image of graphite oxide (C) HR-TEM

image of graphite oxide (200 nm) (D) SAED pattern of graphite oxide


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We used Powder XRD technique to prove the formation of graphite oxide. Absence of a peak around 2θ = 26 (002 plane), and the appearance of the peaks at around 2θ = 42.30 (100 plane) and 9.36 (001 plane) indicating the oxidation of graphite to graphite oxide (Fig. 4).79 Since Raman analysis is a very helpful method for characterization of carbon based materials so we also carried out this analysis for our synthesized graphite oxide. It revealed two prominent characteristic Raman modes. One is a G- band at around 1589.0 cm-1 which is because of stretching of C-C bonds common to sp2 carbon network and the other one is a D-band at around 1360.8 cm-1 which is due to the chaos in that network (Fig. 5). ID/IG, the intensity ratio of D and G bands was also calculated and its value was found to be 1.06 which designates the introduction of anarchy in π-network of graphite.79 TGA analysis of the prepared graphite oxide is shown in Fig. 6 (pink line), its TGA thermograph shows weight loss in two steps. Firstly, below 120 0C shows a weight loss of around 10% due to the loss of the intercalated water molecules and the second drastic weight loss of around 85 % at above 180 0C signifies decomposition of various functional groups and it is characteristic for graphite oxide. A TGA thermograph of graphite was also analyzed and compared with that of graphite oxide. Thermograph of graphite (blue line) shows very negligible loss of weight in the same temperature range as mentioned in the literature.79 For further characterization of prepared graphite oxide we also performed an XPS analysis. In the survey spectrum of graphite oxide (Fig. 7A) two significant peaks corresponding to O and C are observed, which are indicative of oxidation of graphite to graphite oxide. In the spectrum of C 1s, peak at 284.6 eV is attributed to the sp2 hybridized carbon. Other three peaks at 286.6, 287.8 and 288.6 eV are because of three main functional groups of graphite oxide, namely the hydroxyl (C-OH), epoxide (C-O-C) and the carboxyl (HO-C=O) groups respectively (Fig. 7B).80 From the above analysis it can be concluded that graphite oxide is successfully synthesized from graphite powder.



[001]

Graphite Oxide Graphite

G band 100

700 Intensity (a.u)

6000 Intensity

D band

800

7000

5000 4000 3000

80

600

Weight loss (%)

8000

500 400 300

2000

60 40 20

200 0

[100]

1000

100 -20

0

800

20

40

60

80

2 theta degrees

Fig. 4

1000

1200

1400

1600

1800

2000

100

200

-1 Raman Shift (cm )

300

400

500

Temperature (oC)

Fig. 5

Fig. 6

Fig. 4: XRD of graphite oxide Fig. 5: Raman spectra of graphite oxide Fig. 6: TGA of

O 1s

graphite oxide and graphite

C 1s

30000 25000

5000

C-sp2

4000 c/s

20000

c/s

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

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3000

C-OH

15000

2000

C-O-C

10000

1000

5000

COOH

0

0 0

200

400

600

800

1000

Binding energy (eV)

294

292

290

288

286

284

282

280

Binding energy (eV)

(A)

(B)

Fig. 7: (A) Survey spectrum of graphite oxide, (B) Deconvulated XPS peaks of graphite

oxide In an attempt to design a fresh multi-component pathway for the synthesis of fused pyrimidine derivatives, we devised a cascade approach as delineated in the retrosynthetic pathway in Scheme 2. Based on the retrosynthetic breakdown, we envisaged that reaction of (1) and (2) would lead to the formation of i followed by addition of (3) to give desired pyrimidine derivatives (4). This reaction leads to the formation of one stereogenic centre and three new σ bonds in a single operation.


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O R

R

O

N N

X

N X

3

4

+

O

R O +

H NH2

O O i

1

2

Scheme 2: Retrosynthetic pathway for the synthesis of targeted pyrimidine derivatives

We evaluated one-pot three component reaction of 4-cyanobenzaldehyde 1{1}, dimedone 2{1} and 2-aminobenzothiazole 3{1} (Scheme 3). Reaction containing 1:1:1 mixture of above

mentioned reactants was analysed under various conditions. Initially we focussed towards optimization of catalyst concentration and time required to carry out the reaction. A set of reaction was first carried out in absence of any catalyst at 100 0C and it was found that the reaction showed no positive result even after 6h of stirring. Following that we thought of adding catalyst to the reaction mixture and various sets of reactions were carried with different catalyst concentrations ranging from 5-30 mg at 100 0C for 2 h. It was observed that with increasing the catalyst concentration, yield of the product increases. Maximum yield was obtained when 20 mg of catalyst was used. Further increase in the catalyst loading (30 mg) and time (3h) had no significant effect on the yield of the reaction (Table 1). Then, we examined the minimum time required for this transformation. Likewise, reaction time was reduced gradually and it was noticed that at 20 min best conversion was achieved and on further decreasing the time, lower yield was encountered (Table 1). NC O CHO

O N O

CN 1{1}

2{1}

Standardization of various reaction parameters NH2

N N

S S 3 {1}

Scheme 3: Pilot Reaction


4{1,1,1}


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Table 1: Standardization of catalyst concentration and time

a

Time (min.)

Solvent

Temperature (0 C)

Yield (%)a

-

120

-

100

8

2

-

360

-

100

10

2

5

120

-

100

48

3

10

120

-

100

70

4

15

120

-

100

85

5

20

120

-

100

96

6

20

180

-

100

96

7

30

120

-

100

96

8

20

90

-

100

96

9

20

60

-

100

96

10

20

40

-

100

96

11

20

20

-

100

96

12

20

10

-

100

84

13

20

5

-

100

55

Sl

Amount of

No.

catalyst (mg)

1

Isolated yield

Next, effect of solvents and temperature on the pilot reaction was evaluated. It was observed that reaction proceeds moderately in presence of various solvents (5 ml) like toluene, tetrahydrofuran (THF), chloroform, N,N-dimethylformamide (DMF), acetonirile, water, ethanol (EtOH) under refluxing condition, but when reaction was carried out under solventfree reaction condition, maximum yield was obtained at 100 0C (Fig. 8). Better catalytic activity under SFRC can be explained by two factors, these are (a) in absence of solvents,


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there is no dilution effect and the heat required for energy of activation is directly provided to the reactant molecules and (b) the superior dispersal of active reagent sites which provides better contact between catalyst and reactant molecules.

Toluene

Differnt Solvents taken

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


THF

Chloroform DMF

Acetonitrile Water EtOH SFRC 0

20

40

60

80

100

Yield % Fig. 8: Solvent standardization

Now, to choose optimum reaction temperature, model reaction was carried out under SFRC at various temperature ranging from 20 0C to 120 0C. 60 0C was opted to be the most favourable reaction temperature because of higher product yield and lower reaction time (Fig. 9). Further increase in temperature had no significant effect on the product yield.



100 90 80 70

Yield (%)

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

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60 50 40 30 20 10 0 20

40

60

80

100

120

Sets of reaction at various temperature ranges (0 C)

Fig. 9: Temperature standardization

We have also compared the catalytic activity of graphite oxide with that of other solid acid and base catalysts (Table 2). Catalysts like calcium oxide (CaO) and amberlyst-A21 (A 21) showed no positive results even after 2h of stirring but SBA-15, montmorillonite K-10, amberlyst-15 provided poor yield compared to that of graphite oxide. Table 2: Comparison of catalyst a

Sl. No.

Catalyst (20 mg)

Time (min)

Yield (%) b

1

CaO

120

-

2

A-21

120

-

3

SBA-15

120

55

4

A-15

120

53

5

MK-10

120

58

6

Graphite oxide

20

96

a

4-cyanobenzaldehyde (1 mmol), dimedone (1 mmol), 2-aminobenzothiazole (1 mmol), 60 0C, SFRC.

Isolated yield.


b

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It is important to mention that from TGA analysis it was found that synthesized graphite oxide contains 10% of water which is because of moisture present on the surface of the catalyst. In order to confirm whether this water has any role in the reaction or not we carried out the pilot reaction only in presence of water without addition of any catalyst and after stirring the reaction for 2h it showed no positive result. This observation proved that there is no role of water in the reaction. 1. Aldehydes 1 {1-15} CN

Cl

OCH3

Br

Cl

NO2

N

Br

CHO

CHO

CHO

CHO

1 {1}

1 {2}

1 {3}

1 {4}

CHO 1 {5}

CHO 1 {6}

OCH3 O

CHO

CHO

1 {7}

1 {8}

1 {9}

CHO

O

N

OCH3 CHO 1 {10}

CHO

CHO

H3CO

CHO

CHO 1 {11}

NO2

1 {12}

COOCH3 1 {15}

CHO 1 {14}

1 {13}

2. Beta-dicarbonyl compounds 2 {1-3} O O

O

O

O

O

O

O 2 {2}

2 {1}

2 {3}

3. Amine source 3 {1-3} N

N NH2 S 3 {1}

NH2 N H 3 {2}

N NH2 S 3 {3}

Fig. 10: Diversity of Reagents

Based on the proposed retrosynthetic scheme, the optimized reaction conditions were tested on numerous starting materials for the combinatorial metal-free synthesis of a fused pyrimidine derivatives. A wide range of aldehydes 1{1-15}, β-dicarbonyl compounds 2 {1-3} and amine sources 3 {1-3} (Fig. 10) were well tolerated under the optimized reaction parameters providing excellent yields of desired pyrimidine derivatives within shorter period of time (Table 3, scheme 4). Scope of various aldehydes on the desired reaction was also evaluated. Reaction progressed smoothly with both electron withdrawing and electron donating aromatic aldehydes. Position of substituent on the phenyl ring of aryl aldehydes showed no significant effect on the yield and time of the reaction. It has also been observed



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that heteromatic aldehydes, aliphatic aldehydes, and other sensitive aldehydes like N, Ndimethylamino-, 4-chloro-3-nitro-, 2,4,5- trimethoxy-, and aldehydes containing multiple carbonyl groups were very much compatible with the reaction parameters, furnishing desired pyrimidine derivatives in good yield. It is noteworthy to mention that, to create a diverse range of pyrimidine frame work when we used various amine source and β-dicarbonyl compounds, the reaction went smoothly without showing any difficulties. Structures of all the fused pyrimidine derivatives were deduced from elemental and spectral analyses. FT-IR spectra of compound 4{1,1,1} showed absorption peaks at 2228, 1630, 1605 cm-1 which may be due to –CN, -C=O and –C=N stretching. In the 1H NMR spectrum of 4 {1,1,1}, eight aromatic protons appear between δ 7.57–7.01. The methine proton was

observed as a singlet at δ 6.57. Four methylene protons of the dimedone residue appeared as AB system at δ 2.48 as a singlet and as multiplet between δ 2.30–2.16. Its two methyl groups of dimedone were observed as two singlets at δ 1.08 and 0.90 ppm. O

2{1}

N

or

R1CHO 1{1-15}

O

O

X 3{1-3}

O O

R2

NH2

R1

graphiteoxide (20 mg), 60 0C

O

N X N 4{1,1,1}-4{15,1,1}

20-45 min, SFRC X= N, S

2 {2-3} If R2 = -C2H5, 2{2} ; If R2 =-CH3, 2 {3}; R1= Various aryl or aliphatic groups Scheme 4: Graphite oxide catalyzed synthesis of pyrimidine derivatives.

Table 3: Synthesis of various pyrimidine derivatives a

Sl.

Aldehydes

No.

β-dicarbonyl

Amine

compounds

source

Product

Time

Yield

(min)

(%) b

1

1 {1}

2 {1}

3 {1}

4 {1,1,1}

20

96

2

1 {1}

2{2}

3 {1}

4 {1,2,1}

20

94

3

1 {1}

2{2}

3 {2}

4{1,2,2}

20

95


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a

4

1 {2}

2{2}

3 {1}

4{2,2,1}

20

92

5

1 {2}

2{2}

3 {2}

4{2,2,2}

20

93

6

1 {2}

2{1}

3 {2}

4{2,1,2}

25

92

7

1 {3}

2{2}

3 {2}

4{3,2,2}

25

91

8

1 {4}

2{1}

3 {1}

4{4,1,1}

35

88

9

1 {4}

2{1}

3 {2}

4{4,1,2}

35

88

10

1 {4}

2{2}

3 {2}

4{4,2,2}

35

87

11

1 {4}

2{2}

3 {3}

4{4,2,3}

35

88

12

1 {5}

2{2}

3 {1}

4{5,2,1}

30

87

13

1 {5}

2{2}

3 {2}

4{5,2,2}

30

87

14

1 {6}

2{2}

3 {2}

4{6,2,2}

30

85

15

1 {7}

2{3}

3 {3}

4{7,3,3}

20

92

16

1 {8}

2{3}

3 {3}

4{8,3,3}

35

89

17

1 {9}

2{2}

3 {3}

4{9,2,3}

25

92

18

1 {10}

2{2}

3 {3}

4{10,2,3}

40

86

19

1 {11}

2{2}

3 {2}

4{11,2,2}

45

85

20

1 {11}

2{3}

3 {2}

4{11,3,2}

45

83

21

1 {12}

2{2}

3 {2}

4{12,2,2}

30

86

22

1 {13}

2{2}

3 {2}

4{13,2,2}

30

88

23

1 {14}

2{1}

3 {1}

4{14,1,1}

25

90

24

1 {15}

2{1}

3 {1}

4{15,1,1}

25

93

aldehyde (1 mmol), β-dicarbonyl compounds (1 mmol), amines (1 mmol), 20 mg of graphite oxide (catalyst), 60 0C, SFRC. b Isolated yield.

The plausible mechanistic path way has been shown in Scheme 5. It is believable that initially, catalyst graphite oxide increases the electrophilicity of carbonyl groups of aldehydes



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1 {1-15},81-83 which is attacked by β-dicarbonyl compounds 2 {1-3} (in enolic form) to form

Knoevenagel adduct B84 via dehydration of intermediate A. To prove this assumptions, we tested the pilot reaction with acidic and basic graphite oxide (acidic and basic graphite oxide have been synthesized according to the procedure reported by F. Zhang et. al.83). It was observed that basic graphite oxide furnished better result within short period than acidic graphite oxide. It may be due to the fact that, in acidic graphite oxide the reaction proceeds through enolization but in case of basic graphite oxide it follows carbanion path way. Therefore, it has been concluded that the acidic proton of the carboxylic acid of simple graphite oxide activates the carbonyl group of the aldehydes. Amine sources 3 {1-3} then attacks intermediate B in Michael fashion to form another intermediate C, which finally undergoes intra-molecular cyclization followed by dehydration to give the desired product 4.

O

H

O

O

H

O

O

H

O O

O HO

O

O

H

O

O

R H

OH

O

H

O

O

O H

R 2

A

1

H2O O

H

O

= graphite oxide

N R

H2O

X N

4

O

H

O

O

H

3

X NH

O

R

NH2

C

O

O O H O

H

O

O

B

O

Scheme 5: Probable mechanism for the formation of fused pyrimidine derivatives

using graphite oxide In order to test industrial applicability of this procedure we also carried out a gram scale reaction (Scheme 6). For that 4-cyanobenzaldehyde 1{1} (10 mmol), dimedone 2{1} (10


Page 17 of 34

mmol), 2-aminobenzothiazole 3{1} (10 mmol) and graphite oxide (200 mg) were taken and stirred under SFRC at 60 0C for 20 min. After that, the reaction was stopped, catalysts were separated and reaction mixture was purified by column chromatography. Yield of desired product was found to be 88 % indicating its applicability in industries. NC O CHO

O graphite oxide (200 mg),

N NH2 O

S

2{1}

3 {1}

N

60 0C, 20 min, SFRC

N S

CN 1{1}

4 {1,1,1}

Scheme 6: Gram Scale reaction for synthesis of pyrimidine derivatives.

Then in order to make the procedure economically and environmentally more viable, we also carried out a reaction to inspect reusability of graphite oxide. As soon as reaction was complete, the crude reaction mixture was dissolved in 10 ml of chloroform and graphite oxide was separated from it by centrifugation and filtration. This separated graphite oxide was then repeatedly washed with deionised water, ethanol followed by diethyl ether and dried. Catalytic activity of recycled graphite oxide was tested under optimal reaction condition and to our outmost delight it was found that recycled graphite oxide furnished the product in good yields. Likewise this catalyst can be reused in nine more consecutive runs (Fig. 11) without much decrease in catalytic activities. Chemical composition and surface morphology of reused graphite oxide was studied by using Powder XRD, TGA, SEM, HRTEM, and EDX analyses (Fig. S1-Sn) (supporting information) and the obtained results were in good agreement with that of freshly prepared graphite oxide.

100

80

Yield (%)

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


60

40

20

0 1

2

3

4

5 No. of runs

6

7

8

9



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

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Fig. 11: Reusability chart Finally we compared the result of our present catalytic process with that of other reported methodologies, as shown in Table 4. For non-metal acid catalysts (entry 1, 2, 5), the methodologies utilized toxic solvents. However, in entry 3 (boric acid) where water was used as solvent, results in poorer yield for some of the derivatives. For entry 4 and 6 although reaction was reported under SFRC but they required prolonged reaction time for completion (c.f. present methodology). Moreover, all the above mentioned catalysts were non-recyclable. In case of entry 7 and 8 (metal catalysts), catalysts used were hygroscopic, homogeneous and were difficult to handle. Some heterogeneous nanoparticle mediated reactions for the synthesis of pyrimidine derivatives were also reported (entry 9, 10), but they lose their applicability under sustainable conditions due to use of expensive metals in catalytic system (entry 9) or application of ionic liquids as solvents (entry 10). Therefore in comparison to these methodologies, the present protocol utilizes cheap, metal free, heterogeneous recyclable catalyst for the library synthesis of pyrimidine derivatives under sustainable and economic conditions. Table 4: Comparative study of present methodology with other reported in literature SL.

Catalyst used

No.

Nature of

Reaction condition

catalyst

Time

Yield a

(min)

1

Sulfamic acid

Non-metal

Solvent: CH3CN (80 0C)

15-20

90-9562

2

p-toluenesulfonic

Non-metal

Solvent: CH3CN (r.t)

10-45

85-9863

Non-metal

Solvent: Water (r.t)

8-30

75-9564

acid monohydrate 3

Boric acid


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

Silica sulphuric

Non-metal

SFRC (110 0C)

300-360

86-9465

acid 5

Molecular iodine

Non-metal

Solvent: CH3CN (Refluxed)

10-15

69-8469

6

Guanidine

Non-metal

SFRC (110 0C)

120

88-9270

chloride 7

AlCl3

Metal

SFRC(60-70 0C)

66-120

60-8966

8

FeF3

Metal

SFRC (100 0C)

30

70-9767

9

Nano-WO3-

Metal

SFRC (100 0C)

12-20

90-9572

Metal

Solvent: Ionic liquid-

10-15

86-9873

20-45

83-96

supported sulfonic acid 10

Copper nanoparticles

11

Graphite oxide

ethylene glycol ( r.t) Non-metal

SFRC (stirred at 60 0C)

(present method) a

Isolated yield

Conclusion: In conclusion, we have developed a proficient, metal-free, graphite oxide catalyzed procedure for the synthesis of pyrimidine derivatives under solvent-free reaction condition. Easy handling of the catalyst, high reusability, shorter reaction time, solvent-free reaction condition are the plus points of this methodology which makes the process eco-friendly, sustainable and green. Moreover, high tolerance of this procedure towards various functional groups , easy work up, exceptionaly high yields of desired products and good result in gram



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

scale reaction are the added advantages which makes its application in academic and industrial purposes. Experimental Procedure: Preparation of graphite oxide: Preparation of graphite oxide from graphite powder was carried out according to modified Hummer’s method. 1g of graphite (Sigma-Aldrich) and 0.5 g of sodium nitrate was added to 20 ml of concentrated sulfuric acid (98 %). Resulting solution was then kept on ice bath and potassium permanganate (4 g) was added to it slowly over a span of one hour under stirring conditions to avoid any explosion. After completion of addition, reaction mixture was allowed to stirr for one more hour following which, it was heated to 45 0C and the stirring was continued for one more hour. During that time a thick brown paste was obtained. 20 ml of deionized water was then added to it and heated at 45 0C for another 30 min. Finally 180 ml more deionized water was added to the reaction mixture, followed by drop wise addition of hydrogen peroxide (30 %) until color of the solution turns yellowish brown from dark brown. Prepared graphite oxide was recovered by centrifugation, washed with deionized water (3 x10 ml), ethanol (3 x 10 ml) and diethylether (3 x 10 ml). At last it was dried under vacuum and obtained as yellowish brown powder. General procedure for the synthesis of Pyrimidine derivatives 4 {1,1,1- 15,1,1}: A mixture of aldehydes 1{1-15}, β-dicarbonyl compounds 2{1-3} and amines 3{1-3} in the molar ratio of 1:1:1 was taken in a round bottom flask and 20 mg of graphite oxide was added to it. Reaction mixture was then placed on a pre-heated oil bath (60 0C) and stirred under solvent-free reaction condition (SFRC) until completion of reaction (monitored by TLC). Reaction mixture was then cooled to temperature and the crude reaction mass was dissolved


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in chloroform (10 ml). To recover back the catalyst, chloroform layer was centrifuged and filtered. From the residue portion graphite oxide was separated and the filtrate was washed with water (3 x 10 ml), brine (1 x 10 ml) and dried over anhydrous sodium sulphate. Reaction mixture was then concentrated under vacuum and purified by column chromatography using ethylacetate-hexane mixture as the desired eluent. Procedure for catalyst recycling: Following centrifugation and filtration, residue containing graphite oxide was washed with deionized water (2 x 5 ml), ethanol (2x5 ml), diethylether (2 x 5 ml) and dried under vacuum. Recovered graphite oxide (desired catalyst) was then reused in another reaction under similar experimental conditions. Associated Content Supporting Information The Supporting Information is available free of charge on the ACS Publication website. General remarks, characterization of reused graphite oxide, spectral data of compounds, 1H and 13C spectra of compounds.

Acknowledgment:

We would like to thank Department of Chemistry, North-Eastern Hill University (NEHU) and the University Grant Commission (UGC) for supporting this work under the Special Assistance Programme (SAP) (sanctioned no. SERC/F/0293/2012-13) and DST-Purse programme. We are thankful to SERB for financial support (sanctioned no: EMR/2016/005089), and also thankful to the Sophisticated Analytical and Instrumentation Facility (SAIF) of North-Eastern Hill University, ACMS-IIT Kanpur,



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Page 22 of 34

the central instruments facility (CIF) of IIT-Guwahati. We also take this opportunity to thank the Institute of Advanced Study in Science and Technology (IASST), Guwahati for powder XRD analyses. We are also grateful to UGC-non-NET fellowship for offering financial support.

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For Table of contents Use Only A sustainable, metal-free, multi-component procedure for the synthesis of biologically important pyrimidine derivatives has been developed by using recyclable graphite oxide as catalyst under solvent-free reaction condition.


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Metal-Free Greener Syntheses of Pyrimidine Derivatives Using a

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