Chapter-1. Recent synthetic developments of Povarov. Reaction and 2,3-dihydroquinazolinone. derivatives: A short review

Transcription

1 Recent synthetic developments of Povarov Reaction and 2,3-dihydroquinazolinone derivatives: A short review

2 1.1 Introduction Heterocyclic chemistry is a very important branch of organic chemistry accounting for about one-third of contemporary publications. Indeed, two thirds of organic compounds are heterocyclic compounds. Nitrogen, oxygen and sulfur are the most common heteroatoms but heterocyclic rings containing other hetero atoms are too widely recognized. An enormous number of heterocyclic compounds are known and this number is increasing rapidly day to day. In addition, these compounds also comply with the general rule proposed by Huckel. They are highly distributed in natural products and present as a major components in biological molecules. The rich activity of heterocyclic compounds in biological systems is important for pharmaceuticals, and they provide a platform for the rapid exchange of research in the areas of pharmaceutical, medicinal, and organic chemistry. Over 75% of the top two hundred branded drugs in the pharmaceutical industry have heterocyclic fragments in their structures. N-containing family of more than 12,000 natural products includes molecules of a wide ranging (Figure 1) expanse of structural diversity, [1] among the heterocycles found in nature, nitrogen containing heterocycles are the most abundant due to their wide distribution in nucleic acids. This illustrate their involvement in almost every physiological process of plants and creatures. Figure-1 Natural alkaloids 1

3 1.2. Short literature review on Povarov reaction Quinolines rings are present in a number of natural products and synthetic pharmaceuticals. Because of its wide spread biological activities, many methods have been developed for the synthesis of quinolines, the classic methods includes Doebner- Miller reaction, Combes synthesis, Conrad Limpach synthesis, Bischler-Napieralski synthesis, Friedlander synthesis and Povarov reaction etc. The [4+2] cycloaddition reaction of N-aryl imines with nucleophilic olefins is one of the most desirable methods of quinoline preparation, quinolines can be easily held by using Lewis acids. BF 3 -OEt 2 has been mainly applied for this purpose since the revolutionary works of Povarov. [2] Acid-mediated cycloaddition between the azadiene moieties of N-aryl imines and dienophiles also has turn an established route to various tetrahydroquinolines and consequently, quinolines, the major class of heterocycles. Hence, this interaction between N-aryl imines and electron-rich dienophiles (Scheme 1) should be placed as the Povarov reaction. Today, these types of Diels Alder reactions are valuable synthetic routes in organic synthesis, generating heterocyclic rings where the size of the second ring depends on chain broadening. Indeed, multi-component inter and intramolecular Povarov reactions have gained popularity in both diversity-oriented synthesis and target oriented synthesis. Scheme-1 2

4 The reaction mechanism for the Povarov reaction to the quinoline is represented in Scheme 2, initially aniline and benzaldehyde react to form imine. The Povarov reaction requires a lewis acid such as boron trifluoride to activate the imine for an electrophilic addition of the activated alkene. This reaction step forms an oxonium ion which then reacts with the aromatic ring in a electrophilic aromatic substitution, two steps of additional elimination reactions forms the quinoline ring. Scheme-2 Mechanism of povarov reaction. This short review covers the literature, but does not intend to be strictly complete, although its goal is to highlight the improvements in the synthesis of quinoline derivatives via the Povarov reaction Lewis acid catalyzed multicomponent povarov reaction Numerous approaches have been reported in the literature using Lewis acid catalyst for the synthesis of 2-aryl quinoline derivatives. BF 3 -OEt 2 is well known acid catalyst, by using this catalyst many protocols are reported. It has many advantages like mild reaction conditions, easy work-up, a wide range of substrate applicability, and products in good yields. 3

5 D. J. Dibble and co workers [3] reported poly quinolines by using schiff base with acetylene by using lewis acid catalyst with phenylacetylene in the presence of a Lewis acid mediator and the sacrificial oxidant chloranil (Scheme 3). Scheme-3 C. D. Smith and group [4] reported tetrahydroquinoline by using anilines and benzaldehydes, with different norbornenes with high diversity in a multicomponent fashion and are obtained in good yield with high diastereoselectivity (Scheme 4). R 3 R 1 R 3 O NH 2 R 2 H BF 3.OEt 2 20 mol% CH 2 Cl C R 1 H N H H R 2 Scheme-4 Carmindo Ribeiro Borel et al. [5] reported 2-(2-pyridyl)quinolines was achieved via a multi component Povarov reaction of aromatic aldehydes, anilines, and ethyl vinyl ether under boron trifluoride methyl etherate, it shows several advantages over previous reported methods (Scheme 5). Scheme-5 Diego R. Merchan and co workers [6] reported 6,7-methylendioxytetrahydroquinolines, by using iso eugenol as a alkene with aromatic aldehydes and 4

6 anilines in presence of Lewis acid catalyst, racemic products are formed in moderate to good yields (Scheme 6). Scheme-6 Alexey V. Tarantin et al. [7] developed synthesis of 3-ethoxy-carbonyl-5-isopropyl-9- methoxy carbonyl-9,12a-dimethyl-7,8,8a,9,10,11,12,12a-octahydronaphtho [1,2 f] quinoline by using iminoglyoxylate with ethyl vinyl ether in the presence of 15 mol% BF 3 OEt 2 with moderate diastereoselectively (Scheme 7). Scheme-7 Vladimir V. Kouznetsov et al. developed a synthesis of tetrahydro quinolines [8] by using aniline, benzaldehyde and in presence of trans anithole as a alkene source by using lewis acid catalyst BF 3 OEt 2. New different substituted tetrahydroquinolines are reported from the trans anithole under supercritical fluid (CO 2 ) conditions has been reported (Scheme 8). 5

7 Scheme Chiral phosphoric acid catalysed povarov reaction Chiral phosphoric acid (Figure 1) is one among the best catalyst which is using in synthesis of quinolines and it is having so many advantages like stereo selectivity, catalytic amount is enough to carry out reaction effectively. Figure-2 R= C 6 H 4 Cl, tri-isopropyl phenyl, 1-napthyl, G. Dagousset and co workers [9] reported, chiral phosphoric acid catalyzed threecomponent Povarov reactions using enethioureas as dienophile. Different functional bearing aromatic and aliphatic aldehydes, as well as anilines, were tolerated in this catalytic multicomponent reaction, leading to hexahydropyrrolo [3,2-c] quinolines in high yields with excellent diastereo and enantioselectivities (Scheme 9). Scheme-9 6

8 G. Dagousset et al. developed [10] three-component Povarov reaction of aldehydes, anilines, and enecarbamates by using chiral phosphoric acid as a catalyst, this reaction afforded cis-4-amino-2-aryl(alkyl)-1,2,3,4-tetrahydroquinolines in high yields with excellent diastereo selectivities and absolute enantioselectivities (Scheme 10). Scheme-10 Hua Liu et al. developed an approach [11] which combines the advantages of both MCRs and organocatalysis, most important is the highly efficient synthesis of enantiomerically pure (2,4-cis)-4-amino2-aryl(alkyl)-tetrahydroquinolines. Its application has led to the development of a short, efficient synthesis of torcetrapib (Scheme 11). R CbzHN O NH 2 R 1 H 0.1 equivalent chiral phosphoric acid CH 2 Cl 2, 0 0 C R NHCbz N H R 1 Scheme-11 Giulia Bergonzini and coworkers developed [12] an asymmetric Povarov reaction of N- arylimines with 2- and 3-vinylindoles has been developed using a chiral phosphoric acid ((S)-TRIP) as a catalyst. This method makes a versatile synthetic platform for the construction of enantio enriched compounds containing an indole moiety, a very common structure in natural and bioactive molecules (Scheme 12). 7

9 Scheme-12 Hong-Hao Zhang et al. developed a first catalytic asymmetric Povarov [13] reaction of isatin containing 2-azadienes with 3-vinylindoles was reported in the presence of chiral phosphoric acid, which tolerates a wide range of substrates with generally excellent diastereoselectivity and good enantioselectivity (Scheme 13). NH R 2 N R 1 O N R NH 1-napthyl Chirol phosphoric acid 35 mol % O-xylene, 45 0 C, R 1 R 2 N H N O R Scheme Transition and inner transition metal triflates catalysed povarov reaction. Ala Bunescu and co workers developed [14] a two-step synthesis of 2-acyltetrahydroquinoline, through three-component reaction of α-oxo aldehydes, anilines and dienes, by using yetribium triflate as catalyst yields tetrahydro quinolines in good yield (Scheme 14). Scheme-14 8

10 Courtney E. Meyet and co workers [15] reported a alkyl substituted quinolines from anilines, aldehydes, and alkynes. Copper (II) triflate catalyzes this three-component coupling reaction without cocatalyst. Both electron-rich and electron-poor anilines react efficiently in these three-component reaction (Scheme 15). Scheme-15 Heather Twin et al. synthesized pyrrolo[3,4]quinolines [16] through the coupling of anilines with propargylic substituted heterocyclic aldehydes in the presence of metal triflates (Dy(OTf) 3 ). This reaction proceeds through formation of imine and a formal intramolecular aza Diels Alder reaction. This approach was utilized in a total synthesis of quinoline alkaloids (Scheme 16). Scheme-16 Mingsheng Xie et al. reported [17] asymmetric Povarov reaction catalyzed by an N,N - dioxide L 4 Sc(OTf) 3 complex, wide variety of N-aryl aldimines and α-alkyl styrenes were tolerated in this reaction, and the products are in good yields with excellent diastereo and enantioselectivities (Scheme 17). 9

11 1.2.4 Iodine catalysed povarov reaction Scheme-17 Qinghe Gao and group [18] reported highly efficient iodine-mediated formal [3+2+1] cycloaddition for the direct synthesis of substituted quinolines using acetophenones, arylamines, and styrenes has been developed. This synthetic pathway represents an interesting new form of reactivity for the Povarov reaction. This autotandem catalytic process promote three mechanistically distinct reactions in a one pot using molecular iodine (Scheme 18). Scheme-18 Xiang-Shan Wang et al. [19] have showed that a facile method to synthesize exotetrahydroindolo[3,2-c]quinoline derivatives in a three component reaction between an aromatic aldehyde, a reactive amine, and an indole, with iodine as catalyst. The advantages of this method include mild reaction conditions, moderate yields, high stereoselectivity, metal-free catalyst, and operational simplicity (Scheme 19). 10

12 1.2.5 Acid catalysed povarov reaction Scheme-19 Yu-Long Zhao et al. described [20] a proficient synthetic method for 4-((1,3-dithian-2- ylidene)methyl)quinolines, mediated by trifluoromethanesulfonic acid, ethynyl ketene-s,s-acetals can react with various arylamines and aldehydes gives corresponding quinoline derivatives in high yields through arylimine formation, and the products are regiospecific (Scheme 20). Scheme-20 Jing Sun and co workers have showed, [21] three-component reaction of aromatic aldehydes, arylamines and methyl propiolates, mediated by p-toluenesulfonic acid. This acid catalyst efficiently established the imino Diels Alder reaction with β- enamino ester as dienophile. This reaction provides a suitable and stereoselective procedure for the preparation of 2-aryl-4-arylamino-1,2,3,4-tetrahydroquinoline-3- carboxylates in satisfactory yields (Scheme 21). 11

13 Scheme Radical cation catalysed povarov reaction. Xiaodong Jia and group [22] reported a domino process between iminoethyl glyoxylate and N-vinylamides was achieved by using catalytic radical cation salt induced conditions producing a series of quinoline-2-carboxylates. N-Vinylamides were involved as an acetylene equivalent (Scheme 22). Scheme-22 Yaxin Wang et al. describd [23] an efficient synthesis of quinoline-fused lactones and lactams using a radical cation salt-prompted sp 3 C H aerobic oxidation. The catalytic aerobic oxidation of glycine esters and amides was screened for a broad range of substrates. This approach provides one-step access to these biologically and synthetically relevant core structures from simple starting materials (Scheme 23). Scheme-23 12

14 1.2.7 Microwave assisted povarov reaction Abhijit R. Kulkarni have showed that [24] efficient and speedy microwave-assisted synthesis of cyclopentadiene ring-fused tetrahydroquinolines using multi-component Povarov reaction catalyzed by indium(iii)chloride. This protocol has so many advantages like shorter reaction time with high yields (Scheme 24) Montmorillonite as a catalyst Scheme-24 Hans-Georg Imrich et al. asssembled [25] a three-component reaction between a nitrobenzene, different substituted aldehyde, and a dienophile in the presence of iron powder as a reductant and montmorillonite K10 as a catalyst in aqueous citric acid condition undergo Povarov reaction with high stereo-selectivity (Scheme 25). Scheme-25 Sankar K. Guchhait have reported [26] a novel HClO 4 -modified montmorillonitepromoted Povarov reaction, then aerobic dehydrogenation to provide the synthesis of polysubstituted quinolines. HClO 4 -modified montmorillonite as a privileged catalyst, advantages of this method are potential use for promoting povarov reactions and possible successive aerobic dehydrogenation (Scheme 26). 13

15 Scheme Post transition Metal chlorides as catalyst Vellaisamy Sridharan et al. developed [27] a new domino reaction that involves the creation of two C C bonds and the generation of two stereocenters, one of them quaternary, with complete diastereoselectivity and in a single synthetic operation. This transformation can be considered as a novel type of vinylogous aza-povarov reaction, and establishes the foremost example of an α, β-unsaturated hydrazone behaving as the dienophile component in an aza Diels Alder reaction (Scheme 27). Scheme-27 Vladimir V. Kouznetsov and group showed [28] that general protocol for the simple and efficient BiCl 3 -catalyzed synthesis of 2-alkyl-1,2,3,4-tetrahydroquinolines. Synthetic protocols described the one-pot preparation of these tetrahydroquinolines using aliphatic aldehydes, anilines and N-vinyl acetamide in the multicomponent condensation reaction (Scheme 28). 14

16 Intramolecular povarov reaction Scheme-28 Ming Chen and coworkers developed [29] a facile indeno [1,2-b] quinolines by using Povarov reaction through intramolecular cyclisation. Reactions proceeded efficiently in the absence of oxidants, aromatization was achieved by elimination of a leaving group. A broad kind of substitutes may well be incorporated, that permits for a convenient structural modification of straightforward indenoquinolines (Scheme 29). Scheme Short literature review on synthetic efferts of 2,3-dihydroquinazolinones Acid catalysed synthesis Vilas B. Labade et al. developed [30] an efficient synthetic route for 2,3- dihydroquinazolin-4(1h)-ones using 2-morpholinoethanesulfonic acid as a new organocatalyst. The developed synthetic protocol represents a completely unique and extremely easy route for the preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. Additionally, the microwave irradiation technique is with success enforced for ending the reactions in shorter reaction times (Scheme 30). 15

17 Scheme-30 B. V. Subba Reddy and co workers assembled [31] a condensation of 2- aminobenzamide with aldehydes or ketones has been achieved using cellulosesulfonic acid under mild reaction conditions to furnish 2,3-dihydroquinazolin-4(1H)-ones in good yields with a high selectivity. The usage of solid acid catalyst makes this methodology quite straightforward (Scheme 31) Amberlyst-15 mediated synthesis Scheme-31 P. VNS Murthy et al. [32] reported economical and clear technique for the synthesis of 2-aryl 2,3-dihydroquinazolin-4(1H)-ones exploitation amberlyst-15 as a recyclable catalyst. A variety of dihydroquinazolinones were prepared from 2-aminobenzamide and aldehydes under beneath gentle conditions in excellent yields (Scheme 32) Base mediated synthesis Scheme-32 Xiao-Feng Wu and group [33] developed an remarkable and convenient procedure for 2,3-dihydroquinazolin-4(1H)-ones synthesis. Inexpensive inorganic base was applied 16

18 as a promoter and water was used as a green solvent for this transformation (Scheme 33). CN NH 2 Ph O H K 3 PO 4,H 2 O, C, 8 h O N H NH Ph Scheme Chiral phosphoric acid catalysed asymmetric synthesis Figure-3 R= 9-anthracenyl, 2,4,6-(i-Pr) 3 C 6 H 2 Dao-Juan Cheng showed [34] that for the first time, an efficient catalytic asymmetric synthesis of aminal containing heterocyclic compounds from imines. In the presence of 10 mol% of a commercially available (Figure 2) chiral phosphoric acid, a range of aromatic, α, β-unsaturated, and aliphatic imines react with 2-aminobenzamides to grant dihydroquinazolinones in excellent yields (Scheme 34). O NH 2 N X Catalyst (10 mol%) O NH NH 2 Ph H CHCl 3, rt, 24 h N H Ph Scheme-34 Magnus Rueping report on the development [35] of a replacement metal-free, extremely enantioselective, Bronsted acid catalyzed condensation reaction for the synthesis of 2,3-dihydroquinazolinones starting from readily available starting materials. Thus, a highly extremely economical and general approach to valuable enantiomerically 17

19 enriched 2,3-dihydroquinazolinones with preference for the more active S enantiomers has been established (Scheme 35). Scheme-35 Yan Jiang and co workers established [36] the enantioselective synthesis of various substituted Spiro [indoline-3,20-quinazolines]. More significantly, this protocol not solely takes into consideration the speedy building of the chiral Spiro [indoline-3,20- quinazoline] design with potential applications in medicinal chemistry, however additionally provides enantioselective Spiro [indoline-3,20-quinazoline] derivatives for more structural modification and bioassay (Scheme 36) Click reaction Scheme-36 Ahmad Shaabani and co workers developed [37] an efficient condensation reaction of 2-aminobenzamide with various alkyl, aryl, and alicyclic aldehydes or ketones, that provides 2,3-dihydroquinazolin-4(1H)-one derivatives in good yields. This reaction will be classified as a brand new click synthesis as a result this reaction takes place in short times (Scheme 37). 18

20 Scheme Intramolecular Pinner/Dimroth Rearrangement Jian-Hong Tang et al. [38] reported the synthesis of quinazolin-4(3h)-one derivatives, these are obtained by the cyclization of o-aminonitriles with carbonyl compounds using zinc chloride as catalyst by exploitation DMF as a solvent. The reaction scope is significant, and a number of aryl aldehydes could be successfully applied to react with O-aminonitriles to provide quinazolinone compounds with excellent yields (Scheme 38). R 2 R 1 CN NH 2 R 3 O H DMF, ZnCl 2 reflux R 2 R 1 O N H NH R 3 Scheme Co-CNTs as a green reaction medium and a catalyst Javad Safari and group assembled [39] the importance of quinazolinone analogues as synthons in organic synthesis, they have reported the synthesis of a number of these compounds through the Co-CNT catalyzed heterocyclization of O-aminobenzamide with different aldehydes. Short reaction times, mildness, easy work-up are the benefits of this protocol (Scheme 39). Scheme-39 19

21 1.3.8 Ionic liquid mediated synthesis Jiuxi Chen et al. have been synthesized [40] 2,3-dihydroquinazolin-4(1H)-ones in high yields through one-pot three-component cyclocondensation of isatoic anhydrides, ammonia acetate and aldehydes in ionic liquid water solvent system while not the utilization of any further catalyst (Scheme 40). Scheme-40 Junke Wang and group [41] reported poly(4-vinylpyridine) supported acidic ionic liquid catalyst, and employed in the synthesis of 2,3-dihydroquinazolin-4(1H)-ones underneath supersonic irradiation. Effective convalescent and reusability of the catalyst square measure the a number of the benefits of this methodology. Most significantly, the utilization of supersonic irradiation will clearly speed up the reaction (Scheme 41) Using low valent Titanium Scheme-41 Daqing Shi reported a short [42] and facile synthesis of 1,2-dihydroquinazolin-4(3H)- ones via the novel reductive cyclization of O-nitrobenzamides and aldehydes or ketones promoted by TiCl 4 /Zn, benefits of this protocol area unit simply accessible starting materials, convenient operation and moderate to good yields (Scheme 42). 20

22 Scheme Using metal triflates Muthuraj Prakash et al. [43] developed metal catalysed 2,3-dihydroquinazolinones enantioselective synthesis through intramolecular amidation of imines in excellent yields. The scandium(iii)-inda-pybox catalyst provided exceptional catalytic activation of 2-amino N-phenylbenzamide to afford the corresponding 2,3- dihydroquinazolinone with excellent enantioselectivity (Scheme 43) By reductive cyclisation Scheme-43 Yu Hu et al. [44] reported a series of 10-H-spiro[indoline-3,20-quinazoline]-2,40(30H)- diones were synthesized by the reaction of 2-nitrobenzamides with isatins respectively, mediate by SnCl 2-2H 2 O system. A kind of substrates can participate in the process with moderate to good yields (Scheme 44). 21

23 Scheme Nanoparticles used as recoverable catalyst Amin Rostami and cluster [45] reported MNPs-PSA as a eco-friendly, efficient and magnetically recoverable catalyst was used in synthesis of 2,3-dihydroquinazolin- 4(1H)-ones by direct cyclocondensation of anthranilamide and aryl aldehydes or ketones with sensible to high yields in water, benefits of this catalyst are speedy, simple and efficient separation by using an appropriate external magnet (Scheme 45). Scheme-45 M. Z. Kassaee have assembled [46] Al/Al 2 O 3 NPs as an effective catalyst in the onepot multicomponent synthesis of 2,3-dihydroquinazolin-4(1H)-ones. This catalyst is very economical, simply offered, operationally straightforward, and needs gentle reaction conditions. Conjointly the product were got in good yields with short reaction times (Scheme 46). Scheme-46 22

24 Supramolecular synthesis K. Ramesh and group showed an eco-friendly method [47] to synthesize 2,3- dihydroquinazolin-4(1h)-ones in excellent yields, beneath neutral conditions in onepot involving catalysis by β-cyclodextrin in water. Catalyst can be recovered and reused with a little loss of catalytic activity (Scheme 47). O NH 2 CHO -CD/H 2 O O NH NH 2 R C N H R Scheme Grinding under Solvent-Free Conditions Quan-Sheng Ding and group [48] have demonstrated a light and economical ecofriendly synthesis of 2,3-dihydroquinazolin-4(1H)-ones underneath solvent-free conditions, using citric acid as a novel organoacid green promoter, which uses neither harsh conditions nor the use of hazardous catalysts and reagents. Notable benifits of this protocol are wide substrates scope, short interval, inexpensive, water-solubility organoacid, and high yields (Scheme 48). Scheme Ruthenium-catalysed oxidative synthesis. Andrew J. A.Watson reported Ruthenium-catalysed oxidative synthesis [49] for the conversion of alcohols into 2,3-dihydroquinazolines. Reaction conditions are 2- aminobenzamide and alcohol, with crotononitrile, in presence of Ru(PPh 3 ) 3 (CO)(H 2 ) 23

25 permits for the selective formation quinazolinones, and also the product in good yields (Scheme 49) Miscelanious Scheme-49 Moni Sharma et al. developed [50] an efficient cyanuric chloride (2,4,6-trichloro-1,3,5- triazine, TCT) catalyzed approach for the synthesis of 2,3-dihydroquinazolin-4(1H)- one, 2-spiroquinazolinone, and glycoconjugates of 2,3-dihydro- quinazolin-4(1h)-one derivatives. The reaction permits fast cyclization (8 20 min) with 10 mol % cyanuric chloride to give skeletal complexity in excellent yield (Scheme 50). Scheme-50 Matthieu Desroses reported [51] an simple easy and efficient protocol for the synthesis of 2,3-dihydroquinazolinones. This technique, using T3P as the catalyst, has several advantages such as a easy operational procedure, a short reaction time, the employment of very gentle conditions and a simple access to the compounds in good yields (Scheme 51). 24

26 Scheme-51 Someshwar D. Dindulkarwe and group [52] have successfully created a cost-effective protocol for the synthesis of 2,3-dihydroquinazolin-4 (1H) -ones victimization CAN- SiO 2 as a fast reusable catalyst at room temperature. Compare to the earliest known methodologies, this method offers several advantages, together with high production of products, short reaction times, the recyclability of the catalyst (Scheme 52). Scheme-52 Rong Zhang Qiao et al. reported [53] 2-substituted 2,3 dihydro quinazolinones in high yields by condensation of anthranyl amides with aldehydes or ketones in the refluxing 2,2,2-trifluroethanol with none catalyst the gentle and neutral reaction conditions permit the acid or base sensitive substrates to be involved in the reaction timescale (Scheme 53). Scheme-53 25

27 1.4. Scope of the present work: Recent days heterocyclic compounds have become an important source of discovery of drug molecules. Particularly nitrogen containing heterocyclic ring play an important role in bioorganic and medicinal chemistry, especially reports concerning quinoline containing heterocyclic compounds have gradually increased because of their potential biological activity and these quinolines are present in plants as alkaloids best example is quinine and it is used as anti malarial drug by chinese and indian ancient medicine. 2,3-dihydroquinazolinones containing heterocyclic compounds have got so much importance because these quinazolinones are integral part of so many alakaloids and these molecules are used as anticancer agents. Due to the biological significance of these heterocycles so many synthetic efforts have been reported, during the course of our research we have developed a new synthetic protocol for the synthesis of 2-aryl quinoline and 2,3-dihydroquinazolinones derivatives. Propylphosphonic anhydride (T3P )-DMSO mediated one pot three component synthesis of 2-aryl quinolines by modified povarov reaction provides 2-aryl quinolines in a single step from benzyl alcohols, anilines and ethyl vinyl ether mediated by T3P -DMSO as shown in Scheme 83 and evaluated for their anticancer activity against different human cancer cell lines. The results showed that compound F16 was found to be most potent against human cancer cell lines at lower concentrations. 26

28 Scheme- 83 One-pot synthesis of 2, 3-dihydroquinazolin-4(1H)-ones from gemdibromomethylarenes using 2-aminobenzamide is described. Gemdibromomethylarenes used as aldehyde equivalent for the efficient synthesis of 2, 3- dihydroquinazolin-4(1h)-ones, as shown in Scheme 101 and evaluated for their anticancer activity against different human leukemic cell lines. The results showed that compound F27 was found to be most potent against human cancer cell lines at lower concentrations. Where R 1, R= H/Cl/Br/OMe. Scheme-101 ZrO 2 -Al 2 O 3 used as effective nano catalyst for the efficient synthesis of 2, 3- dihydroquinazolin-4(1h)-ones from 2-aminobenzamide using benzaldehyde is described, as shown in Scheme 119, we extended our work to synthesize biologically active piperidine conjugated derivatives, the requisite title compounds F41-44 were synthesized by the reaction of 6-chloro-2-(piperidin-4-yl)-2,3-dihydroquinazolin- 4(1H)-one with different benzene sulfonyl chlorides, benzoyl chlorides, benzyl chlorides as shown in Scheme 120 and the product are obtained in good yields. Later evaluated for their anticancer activity against different human cancer cell lines. The results showed that compound F44 was found to be most potent against human cancer cell lines at lower concentrations. 27

29 R O NH 2 NH 2 R 1 -CHO ZrO 2 -Al 2 O 3 20 mol% Ethanol, reflux R O N H NH R 1 Scheme-119 Scheme

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