part iv : section ashodhganga.inflibnet.ac.in/bitstream/10603/13703/12/12... · 2015-12-04 ·...

Conventional and Non-conventional Organic Synthesis by Some Novel Methods Part IV

Vilas B. Labade 147

Synthesis of Some Heterocyclic Compounds Using Newer Synthetic Strategies

Part IV

Conventional and Non-conventional Organic Synthesis by Some Novel Methods Part IV (A)

Vilas B. Labade 148

Part IV : Section A

Bismuth Triflate Catalyzed Convenient Approach for the Synthesis of Quinazolin-4(3H)-one Derivatives


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4.1.1. Introduction

Quinazolinones have emerged as an important class of nitrogenated heterocycles that

have attracted significant synthetic interest because of their widespread

pharmacological and therapeutic properties.1 4(3H)-Quinazolinones are one of the

important heterocycles and have been shown to possess pharmacologically interesting

properties such as antibacterial, antifungal, antimalarial, antihypertensive,

antidiabetic, anticonvulsant, anti-parkinsonism, antihistaminic and local anesthetic,

analgesic, anti-inflammatory, antiviral, anticancer as well as immunosuppressive

activities.2 Among these, synthetic pelanserine (TR2515)3 is a well established potent

anti-hypertensive, having activity comparable to ketanserin,4 which is an anti-

hypertensive agent used clinically.

At present, some synthetic quinazoline-based drugs, such as metolazone,

quinethazone, and prazosin have achieved medicinal approval for their unique

pharmacological indices, and many others are under clinical evaluation.5 In particular,

gefinitib, i.e. N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)

quinazolin-4-amine (Iressa, ZD1839, Figure 4.1.1) has been recognized as a tyrosine

kinase inhibitor of the epidermal growth factor receptor and has been clinically used

against cell lung cancer with ever increasing popularity.6 Of the different quinazoline

derivatives, quinazolin-4(3H)-ones are the most important intermediates in the

synthesis of different recent anticancer quinazolines.7

Aforementioned wide range of biological activities has stimulated our interest

in new approaches for the synthesis of such quinazolinone derivatives. In the course

of the work, two types of quinazolinone derivatives were planned to synthesize,

namely 2-substituted quinazolin-4(3H)-ones and 2,3-dihydroquinazolin-4(1H)-ones

(Figure 4.1.1, 1 and 2 respectively), utilizing some efficinet and greener catalysts.

Figure 4.1.1. Some interesting quinazoline derivatives.


Vilas B. Labade 150

Being environment friendly bismuth compounds have been used in catalysis

and organic synthesis in the past two decades. Bismuth (III) compounds e.g. Bismuth

chloride (BiCl3), Bismuth nitrate (Bi(NO3)3), Bismuth bromide (BiBr3), Bismuth

triflate (Bi(OTf)3), etc. have been studied as catalysts in a diversity of organic

reactions.8-15 However, up till now there are only several reports on the use of

organobismuth compounds as catalysts in organic synthesis possibly due to the

unstable nature of Bi-C bonds. For these reasons, Bi(OTf)3 is gaining enormous

significance for the synthesis of biodynamic heterocycles.

4.1.2. Literature Review

In accordance with the significance of quinazolin-4(3H)-ones, various synthetic

methods have been developed for the construction of this kind of fused heterocycles.16

Several synthetic strategies for achieving these quinazoline derivatives have been

developed including –

(a) cyclocondensation of anthranilamide with aryl, alkyl or heteroaryl aldehydes

in refluxing ethanol;17

(b) poly(ethylene glycol) supported aza-Wittig reaction;18

(c) intramolecular cyclization of fluorine-containing S-ethyl N-

benzoylisothioureas;19

(d) cyclocondensation of 2-fluorobenzoyl chlorides with 2-amino-N-

heterocycles;20

(e) copper-catalyzed cascade reactions of the substituted 2-halobenzoic acids with

amidines;21

(f) reaction of polymer-bound isothiourea with isatoic anhydride;22

(g) reaction of anthranilic acids and ammonium or triethylammonium N-

aryldithiocarbamates;23 and

(h) one-pot three-component condensation of anthranilic acid, ortho esters and

amines.24-34

Among the various synthetic approaches available for the synthesis of

quinazolin-4(3H)-ones, one pot reaction of anthranilic acid, anilines and triethyl

orthoformate is superior over other reported protocols (Scheme 4.1.1). It is a type of

multi-component reactions (MCRs), which can produce the desired products in a

single step and also the diversity could be achieved simply by varying the reacting

components. Different catalysts like NaHSO4, Amberlyst-15, Yb(III)-resin, Yb(OTf)3,


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[Bi(TFA)3-nbp]FeCl4 ionic liquid, La(NO3)3.6H2O, p-TSA, Keggin-type

heteropolyacid under microwave irradiation, SnCl4.4H2O, SiO2-FeCl3, Zn(ClO4)2,32

SrCl2.6H2O33 and DABCO34 are known to catalyze this condensation reaction.

Scheme 4.1.1. Most common route for the synthesis of quinazolin-4(3H)-ones.

Although the reported methods are valuable by one or other aspect, some of

them still suffer from limitations like unsatisfactory or variable yields, lengthy

reaction time, unsatisfactory substrate tolerance and tedious work-up procedure. It is

therefore of interest to develop a reliable synthetic strategy for the construction of

such fused heterocycles.

4.1.3. Objectives

It has become apparent that quinazolin-4(3H)-ones have been receiving great attention

in the field of medicinal and pharmaceutical chemistry owing to their broad spectrum

of biological/pharmacological activities. In an era, where green methods are

warranted many of the reported methods for the synthesis of these derivatives are

unsatisfactory and hence there is immense scope for further improvement in their

synthetic protocols.

Therefore in continuation of our endeavour35 towards exploitation of

applications of Bi(OTf)3 in organic synthesis and considering the significance of

quinazolin-4(3H)-ones, it was decided to introduce highly efficient synthesis for

obtaining quinazolin-4(3H)-one derivatives using Bi(OTf)3 as a catalyst by

conventional as well as non-conventional sources, i.e. ultrasound and microwave

irradiation techniques.


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4.1.4. Present Work

An efficient and greener protocol for the synthesis of quinazolin-4(3H)-one

derivatives in the presence of bismuth triflate following conventional heating-stirring

method as well as non-conventional ultrasound and microwave irradiation methods is

described (Scheme 4.1.2).

Scheme 4.1.2. Synthesis of quinazolin-4(3H)-one derivatives.

4.1.5. Results and Discussion

For our initial study, reaction of anthranilic acid 1, triethyl orthoformate 2 and 4-

anisidine 3a was considered as a standard model reaction (Scheme 4.1.3). During this

investigation, efforts were mainly focused on exploitation of catalytic activity of

(Bi(OTf)3) for the synthesis of quinazolin-4(3H)-ones. In this regard, initially,

(Bi(OTf)3) was utilized at ambient temperature using different solvents.

COOH

NH2

+EtO OEt

OEt

+

H2N

Bi(OTf)3

N

N

O

1 2 3a 4a

OMe

OMe

Scheme 4.1.3. Standard model reaction.

While performing these experiments, it was observed that reaction in the

presence of ethanol as a solvent gave the desired product in 59% yield (Table 4.1.1,

entry 1). Whereas, water and methanol delivered the product in 56% and 42% yield,

respectively (Table 4.1.1, entries 2-3). In further experiments, when model reaction

was carried out in aqueous methanol and aqueous ethanol, model reaction worked

effectively affording the desired product in 45% and 66% yield (Table 4.1.1, entries

4-5). From this, it was concluded that aqueous ethanol, is far superior to other solvent

systems for completing the model reaction efficiently.


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In our next attempt, effect of temperature on the rate of reaction was

examined. For this purpose the reaction was carried at elevated temperatures i.e. 45,

60, 80 C and reflux temperature. However, increasing the temperature enhanced the

reaction rate substantially and product yield was found to be increased upto 80 C

without any further improvement beyond this temperature (Table 4.1.1, Entries 6-9).

Hence, all the subsequent reactions were performed at 80 C.

Catalyst concentration is a significant factor that exclusively affects the

reaction rate and product yield. To study this, model reaction was carried out at

different concentrations of Bi(OTf)3 such as 1, 2, 5 and 10 mol% and product was

formed in 81, 94, 95 and 92% yield, respectively (Table 4.1.1, entries 8 & 10-12). It

is noteworthy to point out that, reaction proceeds effectively in the presence of only 2

mol% of Bi(OTf)3.

Table 4.1.1. Optimization of reaction conditionsa

Entry Solvent Temperature

(C)

Catalyst

Conc. (mol%)

Time

(min)

Yieldb

(%)

1 Ethanol RT 5 180 59

2 Water RT 5 180 56

3 Methanol RT 5 180 42

4 Aq. methanol RT 5 180 45

5 Aq. ethanol RT 5 180 66

6 Aq. ethanol 45 5 150 63

7 Aq. ethanol 60 5 120 76

8 Aq. ethanol 80 5 45 95

9 Aq. ethanol Reflux 5 45 92

10 Aq. ethanol 80 1 45 81

11 Aq. ethanol 80 2 45 94

12 Aq. ethanol 80 10 45 92 aReaction conditions: 1 (1 mmol), 2 (1.5 mmol), 3a (1.2 mmol) and (Bi(OTf)3)

(5 mol%) in solvent (10 mL); bIsolated yields.

In accordance with the literature, a plausible mechanistic path leading to the

formation of quinazolin-4(3H)-ones can be outlined as shown in Figure 4.1.1.


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O O

OO

HH+

(TfO)3Bi NH2:N

H

H

+H2N

HO

O

:

HN N

OH

O

-

N

N

OH

HN

N

O

H

RR

R

RR

(2) (3) (1)

(4)

(A)

(B)(C)

Figure 4.1.1. Plausible mechanistic path leading to quinazolin-4(3H)-ones.

Encouraged by these results, it was thought to employ activation energy

generated from non-classical energy sources for synthesizing quinazolin-4(3H)-one

derivatives. Non-conventional energy resources like ultrasound and microwave

irradiation techniques have become very popular and useful chemical technologies in

organic chemistry. Considering the well established applications of ultrasound and

microwave activation to promote variety of chemical reactions, we next attempted the

model reaction using optimized reaction conditions under ultrasound as well as

microwave irradiations to investigate whether, (i) the reaction could be accelerated

and, (ii) the product yield could be improved. Assistance of ultrasound irradiations did

not brought significant improvement in the product yield, but it is noteworthy to point

out that the reaction time reduced enormously up to 15 min as compared to

conventional method (50 min). In agreement, reaction under microwave irradiations

also displayed the same results affording the product in good yields by tremendous

reduction in reaction time up to 5 - 10 min. This study clarifies the assistance of

ultrasound as well as microwave energy to accelerate the rate of reaction.

To generalize the synthetic procedure, various electronically divergent anilines

were treated with triethyl orthoformate and anthranilic acid following optimized

reaction conditions. All the substrates were found to be equally amenable to these

conditions under conventional heating method as well as non-conventional energy

sources. Representative results are summarized in Table 4.1.2. Formation of the

products was confirmed on the basis of 1H NMR, 13C NMR and mass spectroscopic

data.


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Table 4.1.2. Synthesis of quinazolin-4(3H)-ones 4(a-l)a

Entry Comp. R Time (min) Yieldb (%)

M.P.c (C) A B C A B C

1 4a 4-OMe 45 15 5 94 93 93 195-196

2 4b 3-OMe 50 15 5 91 91 89 192-194

3 4c 2-Me 45 15 5 95 89 91 138-140

4 4d 3-Me 60 15 5 92 91 88 134-135

5 4e 4-Me 45 15 5 98 96 95 144-146

6 4f 2-Cl 70 15 8 91 90 94 178-179

7 4g 3-Cl 70 15 8 97 89 96 175-177

8 4h 4-Cl 60 15 5 96 91 92 180-181

9 4i 4-F 60 15 5 89 86 91 168-170

10 4j 2-NO2 180 35 12 77 74 80 154-156

11 4k 3-NO2 160 35 10 81 78 84 153-154

12 4l 4-NO2 180 35 12 72 74 76 167-168 aReaction conditions: 1 (1 mmol), 2 (1.5 mmol), 3 (1.2 mmol) and (Bi(OTf)3) (2

mol%) in aq. ethanol (10 mL); bIsolated yields; cMelting points matches with

literature values.

4.1.6. Conclusion

In conclusion, we have developed an exceedingly simple, mild and clean synthetic

protocol for quinazolin-4(3H)-ones. In this method, application of Bi(OTf)3 has been

exploited for obtaining quinazolin-4(3H)-one derivatives. This synthetic strategy

works well under conventional method, as well as by following non-conventional

methods, i.e. ultrasound and microwave irradiation techniques. Major advantages of

the developed synthetic protocol is shorter reaction times, higher product yields, mild

reaction conditions, low catalyst loading, simple work-up procedure and elimination

of harmful organic reagents as well as solvents.


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4.1.7. Experimental

General experimental procedure for the synthesis of 4(a-l)

(A) Conventional method: A mixture of anthranilic acid 1 (1 mmol), triethyl

orthoformate 2 (1.5 mmol), aniline 3 (1.2 mmol) and Bismuth Triflate (0.02 mmol) in

aq. ethanol (25%) (10 mL) was stirred at 80°C. Progress of the reaction was

monitored by TLC (methanol:DCM = 1:19). After time specified in Table 4.1.2,

reaction mixture was left at RT to cool and solvent was removed under reduced

pressure. Then, RM was diluted with water (15 mL) and extracted with DCM (3×10

mL). Organic layer separated was concentrated under vacuum to afford highly viscous

oily mass. Desired compound 4 was purified by column chromatography (eluent,

ethyl acetate:n-hexane = 1:4).

(B) Ultrasound method: A mixture of anthranilic acid 1 (1 mmol), triethyl

orthoformate 2 (1.5 mmol), aniline 3 (1.2 mmol) and bismuth triflate (0.02 mmol) in

aq. ethanol (25%) (10 mL) was subjected to ultrasound irradiations at 60 °C. Progress

of the reaction was monitored by TLC (methanol:DCM = 1:19). After time specified

in Table 4.1.2, reaction mixture was left at RT to cool and solvent was removed under

reduced pressure. Then, RM was diluted with water (15 mL) and extracted with DCM

(3×10 mL). Organic layer separated was concentrated under vacuum to afford highly

viscous oily mass. Desired compound 4 was purified by column chromatography

(eluent, ethyl acetate:n-hexane = 1:4).

(C) MWI method: A mixture of anthranilic acid 1 (1 mmol), triethyl orthoformate 2

(1.5 mmol), aniline 3 (1.2 mmol) and bismuth triflate (0.02 mmol) in aq. ethanol

(25%) (5 mL) was subjected to microwave irradiations (600 W). Progress of the

reaction was monitored by TLC (methanol:DCM = 1:19). After time specified in

Table 4.1.2, reaction mixture was taken out and left at RT to cool down. Solvent was

removed under reduced pressure. Then, RM was diluted with water (15 mL) and

extracted with DCM (3×10 mL). Organic layer separated was concentrated under

vacuum to afford highly viscous oily mass. Desired compound 4 was purified by

column chromatography (eluent, ethyl acetate:n-hexane = 1:4).


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Spectral data for representative compound

3-(4-methoxyphenyl)quinazolin-4(3H)-one (4a)

1H NMR (400 MHz, DMSO-d6)

δ 3.83 (s, 3H), 7.09-7.11 (d, 2H, J = 8.8 Hz, Ar-H), 7.45-

7.47 (d, 2H, J = 8.8 Hz, Ar-H), 7.57-7.62 (dt, 1H, J = 1.2

and 8.4 Hz, Ar-H), 7.73-7.75 (dd, 1H, J = 0.8 and 8.0 Hz,

Ar-H), 7.85-7.90 (m, 1H, Ar-H), 8.18-8.21 (dd, 1H, J =

1.6 and 8.4 Hz, Ar-H), 8.29 (s, 1H). 13C NMR (100 MHz, DMSO-d6)

δ 55.4, 114.3, 121.9, 126.3, 127.2, 127.6, 128.6, 130.3,

134.5, 147.4, 147.7, 159.2, 160.1.

Mass (ES-MS)

m/z 253.1 (M+).

N

N

OOMe

(4a)


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4.1.8. References

1. Undheim, K.; Benneche, T. In Comprehensive Heterocyclic Chemistry II;

Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. eds. Elsevier: Oxford, UK, 1996.

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Davies, N.; Dyke, H. J.; Gilbert, P. J.; Hannah, D. R.; Haughan, A. F.; Hunt, C.

A.; Pitt, W. R.; Profit, R. H.; Ray, N. C.; Richard, M. D.; Sharpe, A.; Taylor, A.

J.; Whitworth, J. M.; Williams, S. C. Bioorg. Med. Chem. Lett. 2005, 15, 751; (c)

Ismail, M. A. H.; Barker, S.; El Ella, D. A. A.; Abouzid, K. A. M.; Toubar, R. A.;

Todd, M. H. J. Med. Chem. 2006, 49, 1526.

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4. (a) Leysen, J. E.; Niemegeers, J. E.; Neuten, J. M.; Lauuron, P. M. Mol.

Pharmacol. 1982, 21, 301; (b) Darchen, F.; Scherman, D.; Laduron, P. M.; Henry,

J. P. Mol. Pharmacol. 1988, 33, 672.

5. (a) Rafi, I.; Taylor, G. A.; Calvete, J A.; Boddy, A. V.; Balmanno, K.; Bailey, N.;

Lind, M.; Calvert, A. H.; Webber, S.; Jackson, R. C.; Johnston, A.; Clendeninn,

N.; Newell, D. R. Clin. Cancer Res. 1995, 1, 1275; (b) Jackman, A. L.; Kimbell,

R.; Aherne, G. W.; Brunton, L.; Jansen, G.; Stephens, T. C.; Smith, M. N.;

Wardleworth, J. M.; Boyle, F. T. Clin. Cancer Res. 1997, 3, 911.

6. (a) Baselga, J.; Averbuch, S. D. Drugs 2000, 60, 33; (b) Kim, R.; Toge, T.

Surgery Today 2004, 34, 293; (c) Camirand, A.; Zakikhani, M.; Young, F.; Pollak,

M. Breast Cancer Res. 2005, 7, 570.

7. Colotta, V.; Catarzi, D.; Varano, F.; Lenzi, O.; Filacchioni, G.; Costagli, C.;

Galeotti, N.; Gratteri, P.; Sgrignani, J.; Deflorian, F.; Moro, S. J. Med. Chem.

2006, 49, 6015.

8. Hisashi, Y. Lewis Acids in Organic Synthesis, Wiley-VCH: Weinheim, 2000.

9. Postel, M.; Dunach, E. Coord. Chem. 1996, 155, 127.

10. Leonard, N. M.; Wieland, L. C.; Mohan, R. S. Tetrahedron 2002, 58, 8373

11. Le Roux, C.; Dubac, J. Synlett 2002, 181.

12. Gaspard-Iloughmane, Le Roux, H. C. Eur. J. Org. Chem. 2004, 2517.

13. Hua, R. M. Curr. Org. Synth. 2008, 5, 1.

14. Gaspard-Iloughmane, H.; Roux, C. L. In Acid Catalysis in Modern Organic

Synthesis, Yamamoto, H.; Ishihara H. eds. Wiley-VCH: Weinheim, 2008.


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15. Suzuki, H.; Matano, Y. Organo Bismuth Chemistry, Elsevier: Amstrerdam, 2001.

16. (a) Stevenson, T. M.; Kazmierczak, F.; Leonard, N. J. J. Org. Chem. 1986, 51,

616; (b) Shimizu, M.; Oishi, A.; Taguchi, Y.; Gama, Y.; Shibuya, I. Chem.

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R.; Besson, T. Tetrahedron 2003, 59, 1413; (d) Kamal, A.; Reddy, K. S.; Prasad,

B. R.; Babu, A. H.; Ramana, A. V. Tetrahedron Lett. 2004, 45, 6517; (e) Yoo, C.

L.; Fettinger, J. C.; Kurth, M. J. J. Org. Chem. 2005, 70, 6941.

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V. N. J. Fluorine Chem. 2007, 128, 748.

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Conventional and Non-conventional Organic Synthesis by Some Novel Methods Part IV (B)

Vilas B. Labade 162

A Facile and Rapid Access towards the Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones

Part IV : Section B


Vilas B. Labade 163

4.2.1. Introduction

As discussed in the previous chapter, quinazolines represent an important heterocyclic

class with diverse biological activities.1 Various quinazolin-4-ones, quinazolin-2,4-

diones and their derivatives are well known to possess an array of physiological

activities. 2,3-Dihydroquinazolinones exhibit a wide range of biological activities,

such as antitumor, antibiotic, antidefibrillatory, antipyretic, analgesic, antihypertonic,

diuretic, antihistamine, antidepressant, and vasodilating behavior.2 They play a key

role in various cellular processes. Furthermore, quinazolinone skeleton is frequently

found in various natural products (Figure 4.2.1). Some examples include the

anticancer compound trimetrexate, the sedative methaqualone, the alpha adrenergic

receptor antagonist such as doxazosin and the antihypertensive agent ketanserin. As a

consequence, they have been very attractive targets in synthetic chemistry in recent

years.

Moreover, a small number of quinazolinones have also been reported as potent

chemotherapeutic agents in the treatment of tuberculosis. For example, 3-aryl-6,8-

dichloro-2H-1,3-benzoxazine-2,4-(3H)-diones, 3-arylquinazoline-2,4(1H,3H)-diones

as antimycobacterial agents3 and quinazolinone derivatives as antitubercular agents.4

The antihyperlipidemic activities of these compounds were also investigated.5 In

particular, the earliest uses in the pharmaceutical area for 2,3-dihydroquinazolin-

4(1H)-ones are antiviral,6 anti-parkinsonism,7 antimicrobial,8 antiinflammatory,9

bronchodilator,10 antihypertensive.11

Figure 4.2.1. Examples of some natural products bearing quinazolin-4-one skeleton.


Vilas B. Labade 164

Development of novel synthetic methodologies to facilitate the preparation of

desired molecule is an intense area of research. In this regard, efforts have been made

constantly to introduce new methodologies that are efficient and more compatible

with the environment.

In the recent years, there has been a growing demand for the development of

more sustainable chemistry, particularly in the synthesis of value added materials, in

order to minimize the great amounts of waste and consecutive treatment.12 In

performing the majority of organic transformations, thermal activation play a crucial

role in making the reaction homogeneous and allowing molecular interactions to be

more efficient. One of the key principles of green chemistry is the elimination of

excessive and wasteful heating during chemical operations or the replacement of

conventional thermal equipments such as oil bath, heating mantle, etc. by non-

conventional sources like microwave irradiations.13


Variety of methods have been developed for the synthesis of quinazolinone

scaffolds.14,15 Of these, the condensation of 2-aminobenzamide with aldehydes or

ketones is one of the simplest and direct methods for the synthesis of 2,3-

dihydroquinazolin-4(1H)-ones (Scheme 4.2.1). Various acid catalysts, such as p-

TSA/NaHSO3,16a TiCl4/Zn,16b CuCl2,16c ionic liquid-water,16d TFA,16e ammonium

chloride16f and chiral phosphoric acids17 have been utilized to accomplish this

transformation. Moreover, Very recently heteropolyacid (H3PW12O40),18a Silica-

bonded N-propylsulfamic acid18b and Cellulose-SO3H18c have been reported to

catalyze this reaction.

Scheme 4.2.1. General route for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones.

However, many of these methods involve the use of expensive reagents,

extended reaction times, high temperatures, and also require tedious work-up

procedures. Therefore, the development of novel methods for the synthesis of 2,3-


Vilas B. Labade 165

dihydroquinazolin-4(1H)-ones is of great importance in view of their potential

biological and pharmaceutical activities.

4.2.3. Objectives

Several methods involving the use of different catalysts have been developed with

their own merits and demerits for the synthesis of 2,3-dihydroquinazolin-4(1H)-one

derivatives. Considering the above discussed significance of 2,3-dihydroquinazolin-

4(1H)-ones, and in continuation of our endeavor towards the development of

ecofriendly synthetic protocols for heterocyclic compounds, it was thought

worthwhile to develop a novel, simple, greener, and expeditious synthetic route for

obtaining 2,3-dihydroquinazolin-4(1H)-one derivatives.

4.2.4. Present Work

Present work involves the synthesis of 2,3-dihydroquinazolin-4(1H)-ones using 2-

morpholinoethanesulfonic acid as an efficient and newer catalyst. Developed

synthetic protocol represents novel and very simple route for the preparation of 2,3-

dihydroquinazolin-4(1H)-one derivatives. In addition, microwave irradiation

technique is successfully implemented for carrying out the reactions in shorter

reaction times.

Scheme 4.2.2. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones.


In search of the best experimental reaction conditions for the preparation of 2,3-

dihydroquinazolin-4(1H)-ones, reaction of 2-amino benzamide 1 and benzaldehyde

2a was selected as a model reaction (Scheme 4.2.3). For this study, we have screened

various acid catalysts bearing sulphonated functionalities owing to their wide spread

catalytic applications in organic synthesis. For this purpose, sulphamic acid,

sulphanilic acid, zinc sulphate and 2-morpholinoethanesulfonic acid were screened.


Vilas B. Labade 166

Scheme 4.2.3. Standard model reaction.

During optimization studies, all the catalysts were examined using ethanol as

solvent at reflux temperature. When sulphamic acid and zinc sulphate were used as

catalyst, reaction rate was very slow and product was obtained in lower yield (Table

4.2.1, entries 1-2). Whereas, sulphanilic acid afforded the desired compound in

acceptable yield but time required for the completion of the reaction was much longer

(Table 4.2.1, entry 3). In comparison, 2-morpholinoethanesulfonic acid (MES)

proved as an excellent catalyst furnishing the product in excellent yield (Table 4.2.1,

entry 4) and therefore, it was chosen as a catalyst of choice for further optimization

studies.

Table 4.2.1. Screening of catalysts and solventsa

Entry Catalyst Solvent Time (h) Yieldb (%)

1 Sulphamic acid Ethanol 8 42

2c Zinc sulphate Ethanol 8 49

3 Sulphanilic acid Ethanol 6 63

4 MES Ethanol 4 78

5 MES Toluene 4 39

6 MES 1,4-Dioxane 4 26

7 MES Acetonitrile 4 48

8 MES Methanol 4 63

9 MES Water 4 67

10 MES Aq. ethanol (50%) 2.5 84 aReaction conditions: 1 (1 mmol), 2a (1 mmol), catalyst (20 mol%) and

solvent (10 mL) at reflux temperature; bIsolated yields.

For evaluation of effect of solvents on model reaction, various solvents such

as, toluene, 1,4-dioxane, acetonitrile, methanol and aqueous ethanol (50%) were

tested at their respective reflux temperatures (Table 4.2.1, entries 5-10). Among the


Vilas B. Labade 167

solvents tested, aqueous ethanol was superior over the other in terms of both product

yield and reaction time (Table 4.2.1, entry 10).

In further attempts, to reduce the reaction time and increase the product yield,

model reaction was tested at different temperatures like RT, 45 ºC, 60 ºC, 80 ºC and

reflux condition. Surprisingly, increase in product yield was observed along with

decrease in the reaction temperature up to 60 ºC (Table 4.2.2, entries 1-5).

To establish the appropriate amount of the catalyst, we investigated the model

reaction using varied concentrations of 2-morpholinoethanesulfonic acid such as 5,

10, 15, 20 and 25 mol%. In this study, formation of the product was observed in 65%,

93%, 91% and 83% yield, respectively. This indicated that 10 mol% of 2-

morpholinoethanesulfonic acid is sufficient to carry out the reaction smoothly.

Table 4.2.2. Screening of temperature and catalyst concentrationa

Entry Temperature (°C) Catalyst Conc. (mol%) Yieldb (%)

1 RT 20 30

2c 45 20 63

3 60 20 88

4 80 20 87

5 Reflux 20 84

6 60 5 65

7 60 10 93

8 60 15 91

9 60 25 83 aReaction conditions: 1 (1 mmol), 2a (1 mmol) and MES in Aq. ethanol

(50%) (10 mL) for 2.5 h; bIsolated yields.

In further set of experiments, model reaction was performed using non-

classical activation energy source, i.e. microwave irradiations. In this experiment,

model reaction was found to proceed effectively within very short reaction time

delivering the desired product in excellent yield. Inspired by this, it was decided to

synthesize number of derivatives following developed reaction conditions by classical

as well as non-classical method.

Probable mechanism for 2-morpholinoethanesulfonic acid catalyzed synthesis

of 2,3-dihydroquinazolin-4(1H)-ones is depicted with the help of Figure 4.2.2.


Vilas B. Labade 168

Figure 4.2.2.Probable mechanism for synthesis of 2,3-dihydroquinazolin-4(1H)-ones.

To further establish the scope of optimized reaction conditions and in order to

generalize the synthetic procedure, variety of electronically divergent aromatic

aldehydes were treated with 2-amino benzamide under conventional and microwave

irradiation method. Presence of electron-withdrawing and electron-releasing groups

on the aromatic rings did not influenced significant effect on the yields. More

importantly, various heteryl aldehydes were observed to be well tolerated under

optimized conditions furnishing the product in good yields. All the results are

compiled in Table 4.2.3. Formation of the desired product was confirmed with the

help of 1H NMR, 13C NMR and mass spectroscopic data.

4.2.6. Conclusion

In summary, we have developed an exceedingly simple and novel synthetic protocol

for 2,3-dihydroquinazolin-4(1H)-one derivatives. To the best our knowledge,

application of 2-morpholinoethanesulfonic acid is reported for the first time to carry

out any organic transformation under conventional as well as non-conventional

method. Remarkable advantages of this synthetic strategy over the others are- (i)

higher product yields, (ii) utilization of microwave irradiations, (iii) decreased

reaction times, (iv) simplified work-up procedure, and (v) most importantly

introduction of newer organic catalyst, which may act as a key for achieving various

organic transformations.


Vilas B. Labade 169

Table 4.2.3. Synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives 3(a-o)a

Entry Compound R

Time

(min) Yielda (%)

M.P.c (C)

A/B A/B

1 3a Ph 150/10 93/95 224-226

2 3b 2-OH-Ph 150/8 93/95 220-221

3 3c 2-NO2-Ph 120/5 88/89 191-192

4 3d 3-NO2-Ph 150/5 85/88 192-194

5 3e 4-NO2-Ph 120/5 91/93 200-201

6 3f 2-OMe-Ph 120/8 96/95 166-168

7 3g 2-Cl-Ph 120/8 86/94 202-204

8 3h 4-N(Me)2-Ph 90/6 92/94 208-210

9 3i 4-OH-Ph 120/8 89/86 >300

10 3j 4-Me-Ph 180/15 91/93 232-233

11 3k 4-OMe-Ph 120/5 93/96 177-178

12 3l 4-Cl-Ph 180/12 89/92 197-198

13 3m 3,4-OMe-Ph 180/12 86/88 211-213

14 3n 4-OH-3-OMe-Ph 120/10 88/90 227-228

15 3o Furfuryl 180/20 81/83 166-167 aReaction conditions: 1 (1 mmol), 2 (1 mmol) and 2-morpholinoethanesulfonic

acid (10 mol%) in 50% aq. ethanol (10 mL); bIsolated Yields; cMelting points

matches with literature values; A=Conventional method and B=MWI method.


Vilas B. Labade 170

4.2.7. Experimental

General experimental procedure for the synthesis of 2-(aryl)-2,3-dihydroquinazolin-

4(1H)-ones 3(a-o)

(A) Conventional method: A mixture of 2-amino benzamide 1 (1 mmol), aldehyde 2

(1 mmol) and 2-morpholinoethanesulfonic acid (0.1 mmol) in 50% aq. ethanol (10

mL) was stirred at 60 C. Reaction progress was monitored by TLC (ethyl acetate:n-

hexane, 1:9). After time specified in Table 4.2.3, reaction mass was allowed to cool

down to room temperature. Thus obtained product was collected by simple filtration

and washed with 50% aq. ethanol (10 mL) This crude product 4 was purified by

crystallization using Aq. ethanol (water:ethanol, 2:8).

(B) MWI method: A mixture of 2-amino benzamide 1 (1 mmol), aldehyde 2 (1 mmol)

and 2-morpholinoethanesulfonic acid (0.1 mmol) in 50% aq. ethanol (5 mL) was

subjected to microwave irradiations (600 W). Reaction progress was monitored by

TLC (ethyl acetate:n-hexane, 1:9). After time specified in Table 4.2.3, reaction mass

was taken out and allowed to cool down to room temperature. Thus obtained product

was collected by simple filtration and washed with 50% aq. ethanol (10 mL) This

crude product 4 was purified by crystallization using Aq. ethanol (water:ethanol, 2:8).


2-phenyl-2,3-dihydroquinazolin-4(1H)-one (3a)


δ 5.75 (s, 1H), 6.65-6.90 (dt, 1H, J = 0.8 and 7.6 Hz,

Ar-H), 6.69-6.72 (dd, 1H, J = 0.4 and 7.6 Hz, Ar-H),

7.08 (s, 1H, exchangeable with D2O), 7.22-7.26 (m,

1H, Ar-H), 7.34-7.41 (m, 3H, Ar-H), 7.48-7.50 (m, 2H,

Ar-H), 7.60-7.62 (dd, 1H, J = 1.6 and 8.0 Hz, Ar-H),

8.24 (s, 1H, exchangeable with D2O). 13C NMR (100 MHz, DMSO-d6) δ 66.6, 114.4, 114.9, 117.1, 126.8, 127.3, 128.3, 128.4,

133.3, 141.6, 147.8, 163.6..

Mass (ES-MS) m/z 225.1 (M+).

(3a)


Vilas B. Labade 171


Vilas B. Labade 172


Vilas B. Labade 173

4.2.8. References

1. (a) Hess, H. J.; Cronin, T. H.; Sciabine, A. J. Med. Chem. 1968, 11, 130; (b) Hori,

M.; Iemura, R.; Hara, H.; Ozaki, A.; Sukamoto, T.; Ohtaka, H. Chem. Pharm.

Bull. 1990, 38, 681; (c) Srivastava, B.; Shukla, J. S.; Prabhakar, Y. S.; Saxena, A.

K. Indian J. Chem. 1991, 30(B), 332; (d) Saxena, S.; Verma, M.; Saxena, A. K.;

Shanker, K. Indian J. Pharm. Sci. 1991, 53, 48.

2. (a) Alaimo, R. J.; Russel, H. E. J. Med. Chem. 1972, 15, 335; (b) Levin, J. I.;

Chan, P. S.; Bailey, T.; Katocs, A. S.; Venkatesan, A. M. Bioorg. Med. Chem.

Lett. 1994, 4, 1141; (c) Maskey, R. P.; Shaaban, M.; Grun-Wollny, I.; Laatsch, H.

J. Nat. Prod. 2004, 67, 1131; (d) Michael, J. P. Nat. Prod. Rep. 2004, 21, 650.

3. Pandey, V. K.; Tusi, S.; Tusi, Z.; Raghubir, R.; Dixit, M.; Joshi, M. N.; Bajpai, S.

K. Indian J. Chem. 2004, 43(B), 180.

4. (a) Srivastava, V. K.; Singh, S.; Gulati, A.; Shankar, K. Indian J. Chem. 1987,

26(B), 652; (b) Pankaj, N.; Palit, P.; Srivastava, V. K.; Shanker, K. Indian J

Chem. 1989, 28(B), 745.

5. Saxena, K. R.; Khan, M. A. Indian J. Chem. 1989, 26(B), 443.

6. Holla Shivarama, B.; Padmaja, M. T.; Shivananda, M. K.; Akbarali, P. M. Indian

J. Chem. 1998, 37(B), 715.

7. Gangwal, A. N.; Kothawade, U. R.; Galande, A. D.; Pharande, D. S.; Dhake, A. S.

Indian J. Heterocycl. Chem. 2001, 10, 291.

8. Singh T, Shalabh Sharma, Srivastava V K and Ashok Kumar, Indian J. Chem.

2006, 45(B), 2558.

9. Tyagi, R.; Goel, B.; Srivastava, V. K.; Kumar, A. Indian J. Pharm. Sci. 1998,

60(5), 283.

10. Raghu Ram, A. R.; Bahekar, R. H. Indian J. Chem. 1999, 38(B), 434.

11. Kumar, A.; Tyagi, M.; Srivastava, V. K. Indian J. Chem. 2003, 42(B), 2142.

12. (a) Horvath, I. T.; Anastas, P. T. Chem. Rev. 2007, 107, 2169; (b) Candeias, N. R.;

Branco, L. C.; Gois, P. M. P.; Afonso, C. A. M.; Trindade, A. F. Chem. Rev. 2009,

109, 2703.

13. Moseley, J. D.; Kappe, C. O. Green Chem. 2011, 13, 794.

14. (a) Witt, A.; Bergman, J. Curr. Org. Chem. 2003, 7, 659; (b) Mhaske, S. B.;

Argade, N. P. Tetrahedron 2006, 62, 9787; (c) Larksarp, C.; Alper, H. J. Org.

Chem. 2000, 65, 2773; (d) Sadanandam, Y. S.; Reddy, K. R. M.; Rao, A. B. Eur.


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J. Org. Chem. 1987, 22, 169; (e) Kalusa, A.; Chessum, N.; Jones, K. Tetrahedron

Lett. 2008, 49, 5840; (f) Liu, X. W.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Angew.

Chem. Int. Ed. 2009, 48, 348; (g) Kshirsagar, U. A.; Argade, N. P. Org. Lett.

2010, 12, 3716.

15. (a) Zhang, Z.-H.; Lu, H.-Y.; Yang, S.-H.; Gao, J.-W. J. Comb. Chem. 2010, 12,

643; (b) Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.; Magnus, N. A.;

Bachheler, L. T.; Diamond, S.; Jeffey, S.; Trainor, G. L.; Anderson, P. S.;

Erickson-Vitanen, K. J. Med. Chem. 2000, 43, 2019; (c) Liu, J. F.; Lee, J.; Dalton,

A. M.; Bi, G.; Yu, L.; Baldino, C. M.; McElory, E.; Brown, M. Tetrahedron Lett.

2005, 46, 1241; (d) Bowman, W. R.; Elsegood, M. R. J.; Stein, T.; Weaver, G. W.

Org. Biomol. Chem. 2007, 5, 103.

16. (a) Hour, M. J.; Huang, L. J.; Kuo, S. C.; Xia, Y.; Bastow, K.; Nakanishi, Y.;

Hamel, E.; Lee, K. H. J. Med. Chem. 2000, 43, 4479; (b) Shi, D. Q.; Rong, L. C.;

Wang, J. X.; Zhuang, Q. Y.; Wang, X. S.; Hu, H. W. Tetrahedron Lett. 2003, 44,

3199; (c) Abdel-Jalil, R. J.; Voelter, W.; Saeed, M. Tetrahedron Lett. 2004, 45,

3475; (d) Chen, J.; Su, W.; Wu, H.; Liub, M.; Jin, C. Green Chem. 2007, 9, 972;

(e) Chinigo, G. M.; Paige, M.; Grindrod, S.; Hamel, E.; Dakshanamurthy, S.;

Chruszcz, M.; Minor, W.; Milton, L.; Brown, M. L. J. Med. Chem. 2008, 51,

4620; (f) Shaabani, A.; Ali Maleki, A.; Mofakham, H. Synth. Commun. 2008, 38,

3751.

17. (a) Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am. Chem. Soc. 2008, 130,

15786; (b) Rueping, M.; Antonchick, A. P.; Sugiono, E.; Grenader, K. Angew.

Chem. Int. Ed. 2009, 48, 908.

18. (a) Zong, Y. X.; Zhao, Y.; Luo, W. C.; Yu, X. H.; Wang, J. K.; Pan, Y. Chin.

Chem. Lett. 2010, 21, 778; (b) Subba Reddy, B. V.; Venkateswarlu, A.; Madan,

Ch.; Vinu, A. Tetrahedron Lett. 2011, 52, 1891; (c) Niknam, K.; Jafarpour, N.;

Niknam, E. Chin. Chem. Lett. 2011, 22, 69.

Conventional and Non-conventional Organic Synthesis by Some Novel Methods Part IV (C)

Vilas B. Labade 175

Part IV : Section C

Silicotungstic Acid Catalyzed Solvent-free Synthesis of 2,4,6-Triaryl Pyridine Derivatives


Vilas B. Labade 176

4.3.1. Introduction

In the recent years, Heteropoly acids due to their unique physicochemical properties

has received considerable attention in different areas of organic synthesis and are

being widely used as homogeneous/heterogeneous catalysts for many acid catalyzed

processes.1 Amongst the various heterogeneous catalysts, heteropolyacids (HPAs) are

the most attractive, because they are commercially available, easy to handle, possess

remarkably lower toxicity, are environmentally friendly, economically cost effective,

they have very high Brønsted acidity, they constitute a mobile ionic structure and

absorb polar molecules easily in the bulk, forming a ‘pseudoliquid phase’.2,3 As a

result, both the surface protons and the bulk protons of HPAs participate in their

catalytic activity, which significantly enhances the reaction rate.

The catalytic properties of heteropoly compounds have been associated with

the characteristics of anionic units and the nature of elements contained in them.

Among them, the compounds of Keggin structure are known for their good thermal

stability, high acidity and high oxidizing capability and are used for various organic

transformations.4 Their significantly higher Brønsted acidity as compared with that of

other traditional solid acids increased their importance in catalytic applications.5

Of the known heteropolyacids, phosphomolybdic acid, phosphotungstic acid

and silicotungstic acid, in particular, have been used in recent years for the synthesis

of various heterocycles.6

Pyridine ring system is of immense interest among heterocyclic moieties,

because of its unique position in medicinal chemistry. Occurrence of their saturated

and partially saturated derivatives in biologically active compounds and natural

products such as NAD nucleotides, pyridoxol (vitamin B6), and pyridine alkaloids

have attracted the attention of synthetic as well as medicinal chemists.7

It has been well established that pyridines can act as pharmaceuticals (as

antimalarial, vasodilator, anesthetic, anticonvulsant, and antiepileptic), dyes, additives

(as antioxidant), agrochemicals (as fungicidal, pesticidal, and herbicidal), veterinary

(as anthelmintic, antibacterial, and antiparasitic), and also in qualitative and

quantitative analysis.7,8

2,4,6-Triarylpyridines are prominent synthons in supramolecular chemistry,

with their Π-stacking ability along with directional H-bonding capacity. In particular,

the attachment of pyridyl rings at the 2- and 6-positions of the central pyridine core


Vilas B. Labade 177

generates terpyridines, whose coordination properties have been greatly exploited for

the development of nanoscale metallosupramolecular architectures.9 In addition, the

excellent thermal stabilities of these pyridines have instigated a growing interest for

their use as monomeric building blocks in thin films and organometallic polymers.10

Recent studies have highlighted the biological activity of triarylpyridines, providing

impetus for further studies in utilizing this scaffold in new therapeutic drug classes.11

These molecules have been found to be useful for the synthesis of DNA

binding ligands, in particular targeting G-quadruplex DNA which has recently

received much attention as a possible target in cancer therapy.12 Their potentially

planar aromatic chromophore is likely to promote p-stacking interactions with the

terminal G-tetrad, and appending various groups to the amino groups may allow for

additional interactions with the loops and grooves of the quadruplex DNA. Guanine-

rich sequences that can potentially form quadruplexes occur in the promoter region of

certain oncogenes and at the 3'-terminus of telomeric DNA, hence making the G-

quadruplex a potentially attractive target for selective anti-cancer therapy and drug

development.13

Owing to aforementioned significance, synthesis of such type of molecules is

becoming popular area of research and hence, chemists are diverting their attention to

search simple routes for their syntheses exploring the applications of different

catalysts by utilizing the concepts of greener chemistry.


Since Krohnke’s original report on the synthesis of 2,4,6-triarylpyridines,14 there has

been a plethora of research targeting their syntheses.15 So far, pyridine ring systems

have been built up by variety of synthetic methods which involve: (i) transformation

of another ring, and (ii) cyclizations classified on the basis of the number of ring

atoms in each of the components being cyclized: (a) from six ring atoms by N-Cα, Cα-

Cβ, or Cβ-Cγ bond formation; (b) by formation of two bonds, from [5+1], [4+2], or

[3+3] atom fragments; (c) by formation of three bonds, from [4+1+1], [3+2+1], or

[2+2+2] atom fragments; and (d) by formation of four bonds, from [3+1+1+1] or

[2+2+1+1] atom fragments.16

Pyridines with 2,4,6-triaryl substitution pattern (Krohnke pyridines) have been

synthesized using various methods and procedures. Traditionally, these compounds

have been synthesized through the reaction of N-phenacyl pyridinium salts with α,β-


Vilas B. Labade 178

unsaturated ketones in the presence of ammonium acetate (NH4OAc).15,17 However,

the pyridinium salts and the unsaturated ketones have to be synthesized first, so this

method is relatively expensive. More recently, several new improved methods and

procedures have been developed for the synthesis of these pyridines: reaction of α-

ketoketene dithioacetals with methyl ketones in the presence of NH4OAc,18 reaction

of N-phosphinylethanimines with aldehydes,19 addition of lithiated β-

enaminophosphonates to chalcones,20 solvent-free reaction between acetophenones,

benzaldehydes, and NH4OAc in the presence of sodium hydroxide,21 and the one-pot

reaction of acetophenones, benzaldehydes, and NH4OAc without catalyst under

microwave irradiation.22

Among all these methods, one pot reaction between acetophenones, aryl

aldehydes and NH4OAc is the well established protocol for the synthesis of triaryl

pyridines (Scheme 4.3.1). Later on, many researchers worked on this reaction to

improve its efficiency. Some protocols based on the use of NaOH have been

developed by Smith and co-workers23 in the presence of PEG-400, whereas, Winter et

al24 employed PEG-300 along with NaOH.

Scheme 4.3.1. Generel reaction for the formation of 2,4,6-triarylpyridines.

Adib et al25 have also described simple and efficient synthesis of 2,4,6-

triarylpyridines using chalcones and ammonium acetate under neat conditions in the

presence of catalytic amount of acetic acid. Nagarapu et al26 carried out this reaction

employing solid-supported perchloric acid (HClO4-SiO2) as a heterogeneous catalyst

at 120 °C under solvent-free conditions. Moreover, Heravi and co-workers27

introduced preyssler type heteropolyacid (H14[NaP5W30O110]) for the synthesis of

2,4,6-triarylpyridines. Catalytic application of wet 2,4,6-trichloro-1,3,5-triazine (TCT)

in the absence of solvent at 130 °C was reported by the group of Maleki and co-

workers.28 Meanwhile, Davoodnia et al29 have performed this reaction using 3-


Vilas B. Labade 179

methyl-1-(4-sulfonylbutyl) imidazolium hydrogen sulfate [HO3S(CH2)4MIM][HSO4],

a Bronsted acidic ionic liquid.

Our group have been engaged in the synthesis of such compounds and in this

regard very recently, we have reported bismuth trifltae catalyzed efficient synthesis of

2,4,6-triarylpyridines30 and the drive still continues.

4.3.3. Objectives

It has become apparent that 2,4,6-triarylpyridines have been receiving great attention

in the field of medicinal and pharmaceutical chemistry owing to their broad spectrum

of biological/pharmacological activities. Hence, in an era, where green methods are

warranted many of the reported methods for the synthesis of 2,4,6-triarylpyridine

derivatives are unsatisfactory and leaves room for further improvement.

Therefore in continuation of our endeavour to develop straightforward

synthetic routes for 2,4,6-triarylpyridines and considering the significance of

silicotungstic acid (H4SiW12O40) as a catalyst, it was decided to establish an efficient

synthesis of 2,4,6-triarylpyridines in the presence of microwave irradiations.

4.3.4. Present Work

A range of symmetrical 2,4,6-triarylpyridines have been synthesized by heating a

mixture of aryl aldehydes 1, acetophenone 2 and NH4OAc 3 in the presence of a

catalytic amount of Silicotungstic Acid (H4SiW12O40) under solvent-free conditions,

either heating at 120 °C or by microwave irradiation method (Scheme 4.3.2).

Scheme 4.3.2. Synthesis of 2,4,6-triaryl pyridines.


Vilas B. Labade 180


In search of the best experimental reaction conditions for the preparation of 2,4,6-

triaryl pyridines, reaction of benzaldehyde 1a, two molecules of acetophenone 2a and

ammonium acetate 3 was preferred as standard model reaction (Scheme 4.3.3). In

initial study, some acid catalysts having different physical properties were screened.

For this purpose, silicotungstic Acid (H4SiW12O40), silver antimony hexafluoride

(AgSbF6) and citric acid were screened in the presence of aqueous ethanol as a

reaction medium.

Scheme 4.3.3. Model reaction.

It was found that citric acid and AgSbF6 delivered the product in 47 and 66%

yield in 3 hrs (Table 4.3.1, entries 1-2). In comparison, H4SiW12O40 completed the

model reaction smoothly affording the desired product in good yield 81% (Table

4.3.1, entry 3). In view of the good catalytic activity of H4SiW12O40 it was chosen for

subsequent optimization studies.

To evaluate the effect of solvent, model reaction was further performed using

H4SiW12O40 in ethanol and water as solvent. Water did not brought the reaction to

completion (Table 4.3.1, entry 5), but in contrast ethanol found to furnish the product

in good yield (Table 4.3.1, entry 4). Considering the increasing importance of

solvent-free reactions in organic synthesis, our next attempt was to examine the

catalytic efficiency of H4SiW12O40 in the absence of solvent. Predictably, it was

observed that in the absence of solvent, reaction rate increased enormously and

desired product was obtained in higher yield (Table 4.3.1, entry 6).

To determine the appropriate concentration of the catalyst, i.e. H4SiW12O40,

model reaction was investigated at different concentrations of H4SiW12O40 such as 1,

2, 5 and 10 mol%. This study revealed that the product was formed in 54, 74, 92 and


Vilas B. Labade 181

93% yields, respectively. This study revealed that 5 mol% of H4SiW12O40 is enough

to carry out the reaction effectively.

Table 4.3.1. Screening of Catalysts and solventsa

Entry Catalyst Solvent Time (h) Yieldb (%)

1 Citric acid Aq. ethanol 3 47

2 AgSbF6 Aq. ethanol 3 66

3 H4SiW12O40 Aq. ethanol 3 81

4 H4SiW12O40 Ethanol 3 75

5 H4SiW12O40 Water 4 Trace

6 H4SiW12O40 Neat-120 C 2 92

7 H4SiW12O40 Neat-MWI 15 min. 91 aReaction conditions: 1a (1 mmol), 2a (1 mmol), 3 (1.5 mmol) and catalyst (5

mol%); bIsolated Yields; Note: 30% Aq. ethanol was used.

In view of increasing interest of organic chemists for utilization of microwave

irradiation technique to promote variety of chemical reactions, our efforts were further

directed towards the activation of model reaction by using this non-conventional

energy source. While performing this experimental part, it was noticed that

microwave technique assisted for the improvement in product yields of some

derivatives, particularly, rate of the reaction was enhanced and reaction time dropped

significantly as compared to conventional heating method (Table 4.3.2).

A mechanism for the formation of triaryl pyridines has been proposed with the

help of Figure 4.3.1. Initially, acetophenone A in the presence of H4SiW12O40 is

converted into its enol form, which gives nucleophilic addition on the aldehyde

molecule B to afford aldol condensation product C. Then second molecule of

acetophenone undergoes Michael addition reaction with C to form the 1,5-diketone

intermediate D. This 1,5-diketone on reaction with ammonium acetate followed by

cyclization and dehydration gives compounds E. Finally, air oxidation of E leads to

the formation of corresponding triaryl pyridine F.

To establish generality of the optimized reaction conditions, various aldehydes

and some acetophenones were allowed to undergo this cyclo-condensation reaction.

Almost all the aromatic aldehydes and acetophenones proved to be amenable to these

reaction conditions. However, no significant substituent effect was found in case of

the all aryl aldehydes (Table 4.3.2).


Vilas B. Labade 182

Ph CH3

O H4SiW12O40

Ph CH3

OH

Ph CH2

OH

Ar H

O H4SiW12O40

Ar H

OH

Ph

O

Ar

Ph

CH2

OH

-H2O

Ph Ph

ArO O

N

Ar

Ph Ph

-H2O

NH4OAc

Ph Ph

ArO NH

Ar

Ph PhN

[O]

-H2OCyclization

H4SiW12O40

(C)(D)

(E) (F)

(A)

(B)

Figure 4.3.1. Suggested mechanism for the synthesis of 2,4,6-triaryl pyridines.

4.3.6. Conclusion

To sum up, we have investigated a new approach for the synthesis of 2,4,6-triaryl

pyridines in the presence of heteropolyacid viz. silicotungstic acid. The remarkable

advantages offered by this method are- (i) solvent-free reaction conditions which do

not need any solvent or reaction medium to achieve the desired compounds, (ii) short

reaction times as compared to other protocols, (iii) simple work up procedure as well

as purification method which avoids the need of column chromatography technique,

affording higher yields of the products. This protocol is a useful alternative to the

existing routes for the synthesis of 2,4,6-triarylpyridines.


Vilas B. Labade 183

Table 4.3.2. Synthesis of 2,4,6-triaryl pyridines 4(a-p)a

Entry Comp. R R1 Time (min) Yieldb (%)

M.P.c (C) A/B A/B

1 4a H H 120/15 92/91 132-134

2 4b 2-Cl H 120/20 95/89 114-115

3 4c 4-Cl H 55/10 92/96 126-128

4 4d 4-Br H 70/15 89/89 101-103

5 4e 4-OMe H 70/15 88/85 97-98

6 4f 4-OH H 165/20 85/78 193-195

7 4g 4-NO2 H 50/10 95/88 96-97

8 4h 4-Me H 150/15 71/79 124-125

9 4i 2-Me H 160/15 89/93 121-123

10 4j Thiophen-2-yl H 165/20 84/64 160-162

11 4k Furfuryl H 150/20 82/68 169-170

12 4l Pyridin-4-yl H 130/10 89/84 188-189

13 4m H 4-Cl 90/15 87/91 190-191

14 4n 4-Cl 4-OMe 120/10 88/69 113-114

15 4o 4-Cl Me 210/15 90/77 200-201

16 4p H Me 150/10 70/74 158-160 aReaction conditions: 1 (1 mmol), 2 (1 mmol), 3 (1.5 mmol) and silicotungstic acid (5

mol%) under solvent-free conditions; bIsolated Yields; cMelting points matches with

literature values; A=Conventional method and B=MWI method.


Vilas B. Labade 184

4.3.7. Experimental

General experimental procedure for the synthesis of 2,4,6-triaryl pyridines 4(a-p)

(A) Conventional method: A mixture of aldehyde 1 (1 mmol), acetophenone 2 (2

mmol), ammonium acetate 3 (1.5 mmol) and silicotungstic acid (5 mol%) was heated

at 120 C for specified time. Reaction progress was monitored by TLC (ethyl

acetate:n-hexane, 1:9). After time specified in Table 4.3.2, reaction mass was allowed

to cool down to room temperature. To the reaction mass, was added chilled Aq.

ethanol (water:ethanol, 7:3) (10 mL) and stirred well for 10 min. Thus obtained

product was collected by simple filtration, thereby removing the catalyst in the

filtrate. This crude product 4 was purified by crystallization using Aq. ethanol

(water:ethanol, 3:7).

(B) MWI method: A mixture of aldehyde 1 (1 mmol), acetophenone 2 (2 mmol),

ammonium acetate 3 (1.5 mmol) and silicotungstic acid (5 mol%) was subjected to

microwave irradiations for specified time. Reaction progress was monitored by TLC

(ethyl acetate:n-hexane, 1:9). After time specified in Table 4.3.2, reaction mass was

taken out from microwave oven and allowed to cool down to room temperature. To

the highly viscous/semi-solid reaction mass, was added chilled Aq. ethanol

(water:ethanol, 7:3) (10 mL) and stirred well for 10 min. Thus obtained product was

collected by simple filtration, thereby removing the catalyst in the filtrate. This crude

product 4 was purified by crystallization using Aq. ethanol (water:ethanol, 3:7).


2,4,6-Triphenylpyridine (4a)


δ 7.46-7.58 (m, 9H), 8.03 (d, 2H, J = 7.2 Hz), 8.18 (s,

2H), 8.31 (d, 4H, J = 7.6 Hz). 13C NMR (50 MHz, CDCl3)

δ 117.1, 127.1, 127.2, 128.7, 128.9, 129.0, 129.1, 139.1,

139.6, 150.2, 157.5.

Mass (ES-MS)

m/z 308.1 (M+).

(4a)


Vilas B. Labade 185


Vilas B. Labade 186


Vilas B. Labade 187

4.3.8. References

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Conventional and Non-conventional Organic Synthesis by Some Novel Methods Part IV (D)

Vilas B. Labade 190

Zirconyl (IV) Chloride Catalyzed Conventional/Non-conventional Synthesis of Pyrano[2,3-c]pyrazole Derivatives

Part IV : Section D


Vilas B. Labade 191

4.4.1. Introduction

Synthesis, reactions and biological activities of 4H-pyran containing molecules afford

an ever-expanding area of research in heterocyclic chemistry. This structural motif

appears in a large number of pharmaceutical agents, drug candidates,1,2 photoactive

materials3 and natural products.4 Specifically, condensed pyrazoles are biologically

interesting compounds and their chemistry has recently received considerable

attention.5,6

In particular, pyrano[2,3-c]pyrazoles constitute one of the privileged

heterocyclic scaffolds known to exhibit important biological activities such as

analgesic,7 antitumor, anticancer,8 anti-inflammatory9 and also serve as potential

inhibitors of human Chk1 kinase.10 Moreover, dihydropyrano[2,3-c]pyrazoles are also

known to play an essential role as antimicrobial11 and insecticidal agents.12 Literature

also reveals that various pyran derivatives have proved to be potential drugs and are

known to possess broad spectrum activities such as anti-allergic,13 cytotoxic,14 CNS

active agents,15 antipyaratic,16 anti-invasive17 and molluscicidal activity.18

Furthermore, heterocyclic compounds bearing 4H-pyran units have played increasing

roles in synthetic strategies to promising compounds in the field of medicinal

chemistry.19 Moreover, the biological activity of fused azoles has led to intensive

research on their synthesis.20

Owing to aforementioned importance of pyranopyrazole derivatives, there is

immense scope for the development of newer synthetic routes for pyrano[2,3-

c]pyrazoles, particularly following combinatorial chemistry. Combinatorial chemistry

is being increasingly applied for the discovery of novel biologically active

compounds. In this context, multicomponent reactions (MCRs) are a powerful tool in

the modern drug discovery process in terms of lead finding and lead optimization.21

The growing environmental awareness in chemical research and

pharmaceutical chemistry, due to their traditionally large volume of waste/product

ratios, is perhaps the ripest area for greening. Green chemistry approaches have

considerable potential not only for the reduction of byproducts, decreasing waste

produced and lowering energy costs, but for the development of new methodologies

for the previously inaccessible materials, using existing technologies.22 Therefore,

there has been great quest towards the development of greener chemical processes,


Vilas B. Labade 192

that are highly valued in medicinal chemistry. A part of this pursuit involves the more

and more exploitation of ecofriendly catalysts for organic synthesis.

Due to easy availability and low toxicity of Zirconium (IV) compounds, Zr

(IV) salts have recently attracted much attention of chemists. Zirconyl (IV) chloride is

moisture stable, readily available and inexpensive oxy-salt of zirconium, and until

now has not been explored in synthetic organic chemistry as a mild and versatile

Lewis acid catalyst. Compared to conventional Lewis acids, zirconyl (IV) chloride

has advantages of low catalyst loading, moisture stability and catalyst recycling.23

Based on the above discussed facts, zirconium compounds are reported as

excellent catalysts for various organic reactions. Among the various zirconium

compounds, zirconyl chloride (ZrOCl2·8H2O) is most effective, relatively non-toxic,

inexpensive and non-sensitive to air.24 A wide range of applications of zirconyl

chloride as a catalyst in organic synthesis are reported. Some of them include

oxidation,25a acylation,25b esterification,25c-d nitration,25e Michael addition,25f Mannich-

type reactions,25g Biginelli reaction,25h synthesis of 2-aliphatic aryloxazolines,25i

synthesis of benzimidazoles,25j synthesis of benzothiazoles,25k and synthesis of bis-

oxazolines.25l

Recently, zirconyl chloride has been proved to be highly effective catalyst for

the synthesis of β-acetamido ketones,26a enaminones and enamino esters,26b α-

aminophosphonates,26c homoallylic alcohols or amines26d and 1,8-dioxo-

octahydroxanthenes.26e

However, there are no examples of the use of zirconyl (IV) chloride as a catalyst

for the preparation of pyrano[2,3-c]pyrazoles. In continuation of our work towards the

development of newer synthetic routes for pyrano[2,3-c]pyrazoles additional attempt

was planned using ZrOCl2·8H2O as a catalyst.


Junek and Aigner27 first established the synthesis of pyrano[2,3-c]pyrazole derivatives

from 3-methyl-1-phenylpyrazolin-5-one and tetracyanoethylene in presence of tri-

ethylamine. Later on, number of synthetic approaches have also been made for the

synthesis of 6-amino-4-aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazoles by the one-

pot multicomponent cyclocondensation of aldehydes, malononitrile, hydrazine

hydrate/phenyl hydrazine and ethyl acetoacetate (Scheme 4.4.1).


Vilas B. Labade 193

Scheme 4.4.1. Most efficient route for the synthesis of pyrano[2,3-c]pyrazoles.

In this regard, Sharanin et al. have employed triethylamine for accomplishing

this reaction.28,29 Recently, Peng and co-workers investigated piperazine30 as a

catalyst for this purpose, whereas, potential ability of piperidine to catalyze this

tranformation was studied by Vasuki and Kumaravel.31 Furthermore, in the last

couple of years, some greener methods have been emerged involving the use of

various catalytic systems such as cupreine,32 per-6-amino-β-cyclodextrin,33 glycine,34

γ-alumina,35a L-proline,35b and nanosized magnesium oxide36 which are having their

own merits and demerits.

Recently, use of silica in water37 as a reusable catalytic system for the

synthesis of pyrano[2,3-c]pyrazoles has been reported by our group.

4.4.3. Objectives

In view of tremendous applications of pyrano[2,3-c]pyrazole derivatives, there is an

urgent need for the exploitation of better synthetic protocols for the preparation of

pyrano[2,3-c]pyrazoles, particularly, in terms of mild reaction conditions, eco-friendly

reaction medium, simple isolation of the product and utilization of non-conventional

technique, particularly, ultrasound irradiation method, etc. In this regard, we wish to

describe the results that successfully led to the development of a novel and simple

method for the synthesis of pyrano[2,3-c]pyrazoles in the presence of zirconyl (IV)

chloride under conventional as well as ultrasonication technique.


Vilas B. Labade 194

4.4.4. Present Work

An environmentally benign four component cyclo-condensation reaction of aldehydes

1, malononitrile 2, ethyl acetoacetate 3, and hydrazine hydrate 4a or phenyl hydrazine

4b has been developed in aqueous medium at reflux temperature for the synthesis of

different pyranopyrazole derivatives using zirconyl (IV) chloride as a catalyst

(Scheme 4.4.2). Use of ultrasound irradiation technique also afforded the good results

in agreement with conventional method.

Scheme 4.4.2. Synthesis of pyrano[2,3-c]pyrazole derivatives.


As shown in Scheme 4.4.3, our investigation was initiated with the optimization of

four component reaction between 4-methoxy benzaldehyde 1a, malononitrile 2, ethyl

acetoacetate 3 and hydrazine hydrate 4a.

Scheme 4.4.3. Model reaction.

Based on our previous work on the synthesis of pyrano[2,3-c]pyrazole

derivatives,37 it was revealed that the reaction is best performed in protic solvent, and

more preferably in aqueous medium, i.e. water. Furthermore, increasing interest of

organic chemists for the use of water as a solvent of choice and its unique properties39

necessitated us to employ water as a reaction medium for the model reaction.


Vilas B. Labade 195

Therefore, to accomplish this goal and considering the significance of green

chemistry, efforts were started with use of ZrOCl2.8H2O in 15 mol% concentration

with respect to substrates. Number of reactions by changing temperature of the

reaction was performed (Table 4.4.1). Model reaction when carried out at room

temperature only trace amount of product was obtained after 2 hrs (Table 4.4.1, entry

1). Whereas, at 40 and 60 °C rate of reaction was slow and formation of the product

was observed in lower to moderate yields (Table 4.4.1, entries 2-3). As expected,

further increase in temperature enhanced the reaction rate and delivered the desire

compound with good results. At 80 °C, 76% yield of the required compound was

achieved in 2 hrs (Table 4.4.1, entry 4), whereas, under reflux conditions only 1 hr

was required to get the product in 81% yield (Table 4.4.1, entry 5).

Catalyst concentration is an important aspect which affects the reaction rate as

well as product yield. Hence, to know the actual concentration of catalyst required for

the reaction, model reaction was performed at different concentrations of

ZrOCl2•8H2O such as 5, 10, 15, 20 and 25 mol% and product was formed in 68%,

79%, 81%, 90% and 89% yield, respectively (Table 4.4.1, entries 5-9). This study

revealed that rate of reaction improved effectively with increase in catalyst

concentration up to 20 mol% without any significant difference on further increase in

catalyst concentration.

Table 4.4.1. Screening of model reaction at variable conditionsa

Entry ZrOCl2.8H2O (mol%) Temp (°C) Time (min) Yieldb (%)

1 15 RT 120 Trace

2 15 40 120 38

3 15 60 120 61

4 15 80 120 76

5 15 Reflux 60 81

6 5 Reflux 60 68

7 10 Reflux 60 79

8 20 Reflux 45 90

9 25 Reflux 45 89 aReaction conditions: 1a (1 mmol), 2 (1 mmol), 3 (1 mmol) and 4a (1

mmol) in water (10 mL); bIsolated Yields.


Vilas B. Labade 196

This success of zirconyl (IV) chloride in water as a solvent may be attributed

to the several factors including hydrophobic interactions which induce favorable

aggregation of organic substrates in water, its polar nature as well as solubility of

catalyst in water. Due to this the organic substrates aggregate and result in their

increased concentration which ultimately creates rapid collisions of the reactants thus

leading to formation of the desired product in very short reaction times.

Diagrammatic representation for possible mechanism involved in zirconyl (IV)

chloride catalyzed synthesis of pyrano[2,3-c]pyrazoles is depicted with the help of

Figure 4.4.1. Literature reveals that the first two steps involved in the reaction path

i.e. formation of Knoevenagel condensation product A and pyrazolone B takes place

simultaneously in the presence of acidic catalyst. These intermediates A and B further

undergo cyclo-condensation to get final compound 5/6.

Figure 4.4.1. Proposed mechanism for the synthesis of pyrano[2,3-c]pyrazoles.

Having these results in hand, our subsequent experimental work was directed

towards the enhancement of the product yield along with reduction in the reaction

time. For achieving this goal, utilization of ultrasound irradiation technique for some

reactions was carried out, since it was the suitable method possessing potential to

enhance efficiency of the developed protocol in terms of product yield as well as

reaction time. During this study, it was observed that most of the reactions completed

efficiently in agreement with conventional method. Moreover, reaction time of almost

all the reactions found to be reduced by 3 to 4 times when compared with the

conventional method (Table 4.4.2).

To demonstrate the efficiency and the applicability of the developed method,

various reactions were performed using electronically divergent aryl aldehydes under


Vilas B. Labade 197

optimized reaction conditions and no obvious electronic effects of the substituent

present on the aromatic ring of aldehyde was observed, affording the products in

almost all cases with excellent yields. All the results are summarized in Table 4.4.2.

Table 4.4.2. Synthesis of pyrano[2,3-c]pyrazole derivativesa

Entry Comp. R

Conventional Ultrasonication

M.P.c (°C) Time

(min)

Yieldb

(%)

Time

(min)

Yieldb

(%)

1 5a 4-OMe-Ph 45 90 15 89 207-209

2 5b Ph 45 86 15 91 241-243

3 5c 4-Cl-Ph 45 88 10 84 231-233

4 5d 4-OH-Ph 60 78 20 81 222-223

5 5e 4-NO2-Ph 45 87 15 92 254-256

6 6a 4-OMe-Ph 60 83 15 87 173-174

7 6b Ph 60 81 15 84 170-172

8 6c 4-Cl-Ph 60 89 20 91 176-178

9 6d 4-OH-Ph 60 82 15 79 212-213

10 6e 4-NO2-Ph 60 84 15 87 193-195 aReaction conditions: 1a (1 mmol), 2 (1 mmol), 3 (1 mmol) and 4a (1 mmol) in

water (10 mL); bIsolated Yields; cMelting point matches with literature values.


Vilas B. Labade 198

4.4.6. Conclusion

In summary, a facile, economic, and green protocol for one-pot multicomponent

cyclocondensation of aldehydes, malononitrile, phenyl hydrazine or hydrazine hydrate

and ethyl acetoacetate is established using zirconyl (IV) chloride as catalyst. Reaction

conditions found to be mild accepting several functional groups present in the wide

range of substrates, without any possibility of unwanted side reactions.

Additionally, developed method offers marked improvements with regard to

product yield, reaction time, and greenness of procedure and provides a better, clean

and practical alternative to the existing protocols. Present work is the first report on

the combined use of ultrasound irradiation and zirconyl (IV) chloride for the synthesis

of pyrano[2,3-c]pyrazoles.


Vilas B. Labade 199

4.4.7. Experimental

General experimental procedure for the Synthesis of pyrano[2,3-c]pyrazoles 5 & 6

(A) Conventional method: A mixture of aldehyde 1 (1 mmol), malononitrile 2 (1

mmol), ethyl acetoacetate 3 (1 mmol), hydrazine hydrate/ phenyl hydrazine 4 (1

mmol), and zirconyl chloride octahydrate (20 mol%) in water (10 mL) was stirred

vigorously under reflux temperature. Progress of the reaction was monitored by TLC

(ethyl acetate:n-hexane, 1:9). After time specified in Table 4.2.2, reaction was

stopped and reaction mass was cooled to room temperature. Reaction mass was then

poured on ice-cold water. Thus formed solid product was collected by simple

filtration and washed with 25 mL hot water. This crude product 5/6 was then purified

by crystallization from 10% Aq. ethanol as a solvent.

(B) Ultrasound method: A mixture of aldehyde 1 (1 mmol), malononitrile 2 (1 mmol),

ethyl acetoacetate 3 (1 mmol), hydrazine hydrate/ phenyl hydrazine 4 (1 mmol), and

zirconyl chloride octahydrate (20 mol%) in water (10 mL) was subjected to

ultrasound irradiations for specified time. Progress of the reaction was monitored by

TLC (ethyl acetate:n-hexane, 1:9). After time specified in Table 4.2.2, reaction was

stopped and reaction mass was cooled to room temperature. Reaction mass was then

poured on ice-cold water. Thus formed solid product was collected by simple

filtration and washed with 25 mL hot water. This crude product 5/6 was then purified

by crystallization from 10% Aq. ethanol as a solvent.


6-Amino-4-(4-methoxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-

carbonitrile (5a)


1.76 (s, 3H, -CH3), 3.71 (s, 3H, -OCH3), 4.51 (s, 1H), 6.79 (s,

2H, -NH2), 6.84 (d, 2H, J = 8.0 Hz, Ar-H), 7.04 (d, 2H, J = 8.0

Hz, Ar-H), 12.04 (s, 1H, -NH). 13C NMR (50 MHz, DMSO-d6+CDCl3)

δ. 8.8, 34.7, 53.8, 57.7, 94.7, 96.5, 112.5, 119.7, 127.4, 134.7,

134.8, 153.8, 157.0, 159.5.

Mass (ES-MS)

m/z 283.2 (M+).

(5a)


Vilas B. Labade 200


Vilas B. Labade 201


Vilas B. Labade 202

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LIST OF PUBLICATIONS

1. Cesium fluoride catalyzed aza-Michael addition reaction in aqueous media.

Labade, V. B.; Pawar, S. S.; Shingare, M. S. Monatsh. fur Chem. 2011, 142,

1055-1059.

2. Citric acid: an efficient and biodegradable catalyst for the convenient synthesis of

1,5-benzodiazepines in water. Labade, V. B.; Shinde, P. V.; Pawar, S. S.;

Shingare, M. S. Chem. Biol. Interface 2011, 1, 349-354.

3. Bismuth triflate: an efficient catalyst for the solvent-free synthesis of 2,4,6-triaryl

pyridines and selective acetalization of tetrazolo[1,5-a]-quinoline-4-

carbaldehydes. Shinde, P. V.; Labade, V. B.; Gujar J. B.; Shingate, B. B.;

Shingare, M. S. Tetrahedron Lett. 2012, 53, 1523-1527.

4. Application of unmodified microporous molecular sieves for the synthesis of poly

functionalized pyridine derivatives in water, Shinde, P. V.; Labade, V. B.;

Shingate, B. B.; Shingare, M. S. J. Mol. Catal. A: Chem. 2011, 336, 100-105.

5. An efficient synthesis and antibacterial screening of novel oxazepine α-

aminophosphonates by ultrasound approach Sonar, S. S.; Sadaphal, S. A.;

Labade, V. B.; Shingate, B. B.; Shingare, M. S. Phosphorus, Sulfur, Silicon

Relat. Elem. 2010, 185, 65-73.

6. Synthesis of bis(indolyl) methanes using aluminium oxide (acidic) in dry media.

Sadaphal, S. A.; Kategaonkar, A. H.; Labade, V. B.; Shingare, M. S. Chinese

Chem. Lett. 2010, 21, 39-42.

7. Synthesis and antimicrobial activity of tetrazolo[1,5-a] quinoline-4-carbonitrile

derivatives, Kategaonkar, Am. H.; Labade, V. B.; Shinde, P. V.; Kategaonkar, At.

H.; Shingate, B. B.; Shingare, M. S. Monatsh. fur Chem. 2010, 141, 787-791.

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