REVIEW OF LITERATURE

Thirupathi, G. et al. (2013), reported that L-tyrosine has been utilized as an

efficient and eco-friendly catalyst for the Knoevenegel condensation of aryl

aldehydes with barbituric acid and 2- thio barbituric acid containing cyclic

active methylene groups in aqueous medium at room temperature to produce

5-arylidene-pyrimidine-2,4,6-triones and 5- arylidene -2- thioxo-dihydro-

pyrimidine 4,6- diones (22).

Pierre Lacotte, et al. (2013), described that a small library of dihydro

pyrimidin-2-ones (DHPMs) was synthesized and evaluated for their potency to

block iodide entrapment in rat thyroid cells. A newly synthesized derivative

exhibited a remarkably strong activity with a half maximum inhibitory

concentration value (IC50) of 65 pM. This study provides new insight for the

development of antithyroid drugs as well as for the synthesis of novel

pharmacological tools designed to investigate iodide transport mechanisms at

cellular and molecular levels (18).

Tanuja Kadre, et al. (2012), stated that the synthesis was performed in the

presence of TBAB as catalyst using microwave.The three-component

condensation of β-ketoamides, substituted benzaldehydes and thiourea were

catalyzed by cerium chloride to afford the monastrol based dihydro

pyrimidones. In the present work the structural modifications on the monastrol

backbone are carried out at the ester moiety at C5 position and aryl group at C4

position (21).

The monastrol based dihydro pyrimidones were selected by the development

therapeutic programme of National Cancer Institute (NCI) and tested on a 60

human tumour cell line screen. The in vitro cytotoxic evaluation of the

compounds were carried out on the selected human cancer cell lines of lung,

breast, skin and colon.

Hiren M Marvaniya. et al. (2011), stated that pyrimidine nucleus was

synthesized by Biginelli reaction. This product was subjected for alkaline ester

hydrolysis and these derivatives on treatment with thionyl chloride and

substitution by different secondary amines produced final desired compounds.

The in vitro antihypertensive and calcium channel blocking activity have been

done by IC50 measurement method with nifedipine as standard (9).

Niharika I Singh et al. (2011), well informed a simple and an efficient method

that was developed for the synthesis of various 1, 2, 3, 4‐tetrahydropyrimidine

derivatives prepared from urea and substituted aldehydes using microwave

irradiation technique. The series of Ethyl 1‐ (2‐hydrazine‐2‐oxo ethyl)

‐6‐methyl ‐2‐oxo‐4-phenyl ‐ 1, 2, 3, 4 - tetrahydro pyrimidine-5‐carboxylate

synthesized, confirmed by analytical and spectral data and evaluated for their

calcium channel inhibition using nifedipine as an analog (14).

Sara Rafieepour et al. (2011), statemented that thirty nine novel 1, 2, 3, 4-

tetrahydro pyrimidinone (thione) s which were subjected to conformational

studies and important dihedral angles and bond lengths were investigated and

the values obtained were explainable. Results of this work confirmed a twisted

boat tetrahydropyrimidine ring conformation with an axial C4 substituent for

most of the compounds. This substituent was oriented toward the C5 atom. The

carbonyl group located on the C5 substituent and the C5=C6 bond had both s-

cis and s-trans conformation in the studied molecules (20).

Bruno Piqani et al. (2011), detailed the high efficiency of the diversity-

oriented synthesis achieved by conducting a multicomponent reaction for

improved atom economy, under microwave heating for fast reaction and with

fluorous solid-phase extractions (F-SPE) for ease of purification (1).

Rajasekaran, S. et al. (2011), alerted a series of some dihydro pyrimidine - 2

(1H)-thione derivatives that had been synthesized and characterized on the

basis of IR and NMR spectral data. Antitubercular and antibacterial activities

were performed by microbroth dilution and cup-plate method respectively.

The compounds were also screened for antioxidant activity by DPPH method

(19).

Mirjalili, B. F. et al. (2011), clued up 3, 4 – dihydro pyrimidin-2(1H)-ones and

3, 4 –dihydro pyrimidin – 2 (1H) - thione and were synthesized under solvent

free condition in the presence of nano-silica supported boron trifluoride (nano-

BF3.SiO2). The reactions were carried out at 80° C for 15 min under solvent

free condition. This method had some advantages such as good to excellent

yield, mild reaction condition, ease of operation and workup, short reaction

time and high product purity (12).

Maria Alfaro Blasco et al. (2010), practised the first enantio selective

biocatalytic synthesis of (S)-monastrol that was developed via an unexpected

and unusual enzymatic pathway as suitable route, whereas attempts for a direct

hydrolysis of racemic monastrol were not successful, formation of racemic O-

butanoyl monastrol and subsequent enantio selective hydrolysis furnished O-

butanoyl (S)-monastrol with 97 %. Cleavage of the O-butanoyl moiety then

gave the desired (S)-monastrol with 96 % (11).

Nazeruddin, N Gulam Mohammed et al. (2010), informed an efficient microwave

assisted one pot synthesis of dihydro pyrimidine-2 (1H) from aldehydes,

diketones and urea/thiourea using 5-sulphosalicylic acid as a catalyst and

compared it to classical Biginielli reaction. The new method has an advantage of

good yield and short reaction time (13).

Heda, L. C. et al. (2009), well versed the synthesis of some halo substituted indole

dihydro pyrimidines and evaluated their antimicrobial activity. The minimum

inhibitory concentration (MIC) was determined by micro dilution technique in

Mueller-Hinton broth (8).

Patil, P. A. et al. (2009), detailed that eight new 4-substituted aryl-6-methyl-2-

pyrimidinone-5 - (N-p-tosyl) carbohydrazides were synthesized in a three step

reaction. Their structures were confirmed by IR, 1H- NMR, 13C NMR and

Mass. The compounds were tested for antihypertensive activity by non-

invasive tail-cuff, and evaluated by carotid artery cannulation method for

determining the diastolic blood pressure. Hypertension was induced by

DOCA-salt. Anti-inflammatory activity was carried out by carrageenan

induced rat-paw oedema method. Investigation for analgesic activity and acute

ulcerogenesis was carried out (15).

Eman Moustafa Hassan Abbas et al. (2008), conscioused salicylaldehyde and

some of its derivatives react with urea (or thiourea) and ethyl acetoacetate (the

Biginelli reaction) to give products that depend on the type of the substituent

in the ortho-position to the hydroxyl group. Aldehydes having oxygen-bearing

substituents ortho to the hydroxyl group (e.g., OCH3, NO2, COOH) undergo

chelation with the hydroxyl proton and lead to 4-aryl-6-methyl-4-aryl-2- oxo-

1, 2, 3, 4-tetrahydro pyrimidine-5-ethyl carboxylate (the classical Biginelli

product) (4).

Karami, B. et al. (2008), accounted the catalytic activities of tungstate sulfuric

acid in synthesis of dihydro pyrimidinthiones under solvent free conditions at

80o C. These mild and heterogeneous reactions were completed after 30-150

minutes with high yields (10).

Deyanira Angeles-Beltrán et al. (2006), studied the catalytic ability of

ZrO2/SO4 - to promote solvent less three-component condensation reactions of

a diversity of aromatic aldehydes, urea or thoiurea and ethyl aceto acetate. The

sulfated zirconia catalyst can be recovered and recycled in subsequent

reactions with a gradual decrease of activity (3).

Dennis Russowsky et al. (2006), notified the synthesis and differential

antiproliferative activity of monastrol, oxo-monastrol and eight oxygenated

derivatives on seven human cancer cell lines. For all evaluated cell lines,

monastrol was shown to be more active than its oxo-analogue, except for HT-

29 cell line, suggesting the importance of the sulfur atom for the

antiproliferative activity (2).

Peyman Salehi et al. (2003), awakened that silica sulfuric acid efficiently

catalyses the three-component Biginelli reaction between an aldehyde, a

dicarbonyl compound and urea or thiourea in refluxing ethanol to afford the

corresponding dihydro pyrimidinones in high yields. The catalyst is reusable

and can be applied several times without any decrease in the yield of the

reaction (16).

Zoltan Maliga, et al. (2002), alerted monastrol appears to inhibit microtubule-

stimulated ADP release from Eg5 but does not compete with microtubule

binding suggesting that monastrol binds a novel allosteric site .(S)- monastrol,

as compared to the (R)-enantiomer is more potent inhibitor of Eg5 activity in

vitro and in vivo (24).

Fabio S Falsone, et al. (2001), awared that 4-aryldihydro pyrimidine-2-(1H)-

ones were synthesized by one-pot, polyphosphate ester mediated Biginelli

three-component condensation. The yields of dihydro pyrimidones obtained

via this novel protocol were significantly higher than those utilizing the

conventional ethanol/HCl method. The mechanism of the polyphosphate ester

based method and the formation of side products were also described (6).

Haixia Lin, et al. (2000), observed a mild and efficient catalytic method for

synthesis of 5-alkoxy carbonyl - 4 - aryl-3, 4-dihydro pyrimidin-2(1H)-ones

using montmorillonite as catalyst (7).

The table contains the list of acid catalyst used so far to increase the yield in

Biginelli’s reaction (Table no:1)

Table 1. List of acid catalyst used

S.No Catalyst

1. Cu(OTf)2

2. BF3·OEt2

3. LaCl3·H2O

4. ZrCl4

5. Sr(OTf)2

6. In(OTf)3

S.No Catalyst

7. ZnCl2

8. FeCl3·6H2O

9. RuCl3

10. Ce(NO3)3·6H2O

11. Tungstate sulfuric acid

12. Ceric ammonium nitrate

13. Ultrasound

14. Acidic clay montmorillonite KSF

15. InCl3

16. InBr3

17. LnCl3

18. Yb(OTf)3

19. H2SO4

20. Conc.HCl

21. Zirconium(IV)chloride

22. Ytterbium(III)-resin

23. 1-n-butyl-3-methyl imidazolium tetrafluoroborate (BMImBF4)

24. Hexafluorophosphorate (BMImPF6) in ionic liquids

25. Mn(OAc)3·2H2O

26. Lanthanide triflate

27. Lanthanum chloride

28. Indium (III) chloride

29. Glacial acetic acid

30. Polyphosphate ester

31. Tetra-butyl ammonium bromide TBAB

32. YbCl3

33. 12-tungstophosphoric acid

34. 12-molybdophosphoric acid

35. CuCl2

36. CoCl2

S.No Catalyst

37. NiCl2

38. Sc(III)triflate

39. 1-n-butyl-3-methylimidazolium saccharinate (BMImSac)

40. PPA

41. AlCl3

42. H3BO3

43. ZrCl4

44. NH4Cl

45. NBS

46. In, Bi, Cu

47. 5-Sulphosalicyclic acid

48. Solid-support

49. Ionic liquids

50. LiBr

51. MgBr2

52. CaF2

53. Mn(OAc)3

54. ZnI2

55. CdCl2

56. PhB(OH)2

57. CuI

58. LiClO4

59. CuSO4.5H2O

60. Cu(OTf)2

61. Al(HSO4)3

62. Trimethylsilyl triflate

63. LaCl3·H2O

64. (NH4)2CO3

65. NaCl

66. {Fe2CuO} clusters

S.No Catalyst

67. Heteropoly acids

68. Silica sulfuric acid

69. Ferric chloride/tetraethyl orthosilicate

70. Sr(OTf)2

71. In(OTf)3

72. RuCl3

73. Clay-SmCl3 6H2O System

74. Sc(III)triflate

75. Task Specific room temperature Ionic Liquids (TSILs)

76. 1-n-butyl-3-methylimidazolium saccharinate (BMImSac)

77. L-tyrosine

78. Sulfated Zirconia

MECHANISTIC STUDIES

The first mechanistic studies of the Biginelli reaction were conducted by Folkers and

Johnson forty years after Biginelli’s initial report. Four possible combinations of the three

reaction components were examined for the generation of dihydro pyrimidine (Figure 1 & 2):

(A) the termolecular reaction between benzaldehyde, ethyl acetoacetate and urea, (B) the

combination of ethyl acetoacetate and benzal-bisurea, (C) the reaction of benzaldehyde and

ethyl β-carbamido crotonate and (D) the reaction of ethyl α-benzal aceto acetate and urea.

Folkers and Johnson based their mechanistic conclusions on reaction yields and visual

observation. They proposed that the simultaneous combination of the three reaction

components in A was improbable. D was ruled out on the basis of the low reaction yields (2

%).In contrast, B and C gave high yields of 6 (80 %). The authors noted that B might have

undergone fragmentation of the benzal-bisurea, regenerating the three reaction components,

which might have then formed the product by another pathway. Further, the authors posit that

the β-carbamidocrotonate in C hydrolyzes to the original three reaction components.

Therefore, they concluded that 6 were likely formed from cyclization of 5, which could be

generated from either B or C. The second mechanistic proposal was suggested by Sweet and

Fissekis forty years after Folkers’ pioneering work 4. This proposal involved an aldol

condensation between benzaldeyde and ethyl acetoacetate to form a stabilized carbenium ion

7. Trapping with N-methylurea gives 8, which could cyclize to form 9 (Figure 2). The

observation that independently prepared 10 reacts with N-methylurea under acidic conditions

to generate 9 provides evidence in support of this mechanism. Evidence against this

mechanism was provided by Kappe, 5 who found that reaction of 10 with N-methylthiourea

produced thiazine 11 and not dihydropyrimine 12, which was the observed product under

standard Biginelli conditions (catalytic amounts of HCl, refluxing ethanol) .

Figure 1. Mechanism of Biginelli

Figure 2. The ‘Atwal-Modification’ of the Biginelli Reaction

O

+CH3

O

O

O

CH3

O

OCH3

O

CH3

+CH

+

OCH3

O

CH3

O

CH+

OCH3

O

CH3

OH

O

NH2

NH2

O

CH3O

O

CH3

NH

ONH2

NH

NH

CH3 O

O

CH3

Figure 3.Sweet and Fissekis Mechanism

O

+

O

NH2

NH2

NH

OH

O

NH2

NH+

O

NH2

CH3

O

O

O

CH3

NH

CH3

O

O

CH3

CH3O

O

NH2

NH

NH

CH3 O

O

CH3

Figure 4. Kappe Mechanism (17).

Figure 5. Conformational analysis of dihydro pyrimidin-2-ones

The ester group is in coplanar arrangement with the double bond of the dihydro

pyrimidine ring (carbonyl group cis or trans with respect to the C5_C6 double bond).where

the methyl substituent on the C4-aryl ring adopts either a syn- (sp) or antiperiplanar (ap)

orientation with respect to C4_H . In all four conformations, the aryl ring is positioned

axially, perpendicular to and (nearly) bisecting the half-boat-like dihydro pyrimidine ring (no

minima were found for equatorially arranged C4-aryl rings). It should be noted that the

overall conformational and structural preferences observed for DHPMs are quite similar to

those found for dihydro pyridines, again demonstrating the close structural relationship of the

two heterocyclic systems. During the mid 1980s, interest was originally focused on 4-aryl-1,

4-dihydro pyrimidine-5-carboxylate calcium channel blockers which closely mimic the

dihydropyridine (DHP) scaffold. Additionally a substituent on N3 of the dihydro pyrimidine

ring was found to be a strict requirement for the activity and the order of potency for the 2-

hetero atom was S\O\N.In the test samples (dihydro pyrimidine ring) there are two nitrogen

(N) atoms which is bioisosteric with (CH) and one methyl group (CH3) which is bioisosteric

with ketone (C=O) of nifedipine (dihydro pyridine ring). The ester (-COO-) linkage of

nifedipine has been replaced by amide (-CONH-) linkage in the test compounds (20).

Figure 6. Conformational analysis of dihydro pyrimidin-2-ones

The C5 position of pyrimidine nucleus is an attractive target for modification as

it is located at the major groove surface in the duplex form and will not directly inhibit

the hydrogen bonding in an A: T base pair.In the family of heterocyclic compounds

nitrogen containing heterocycles are an important class of compounds in the medicinal

chemistry and also have contributed to the society from biological and industrial point which

helps to understand life processes. Biginelli compounds leading to the development of

nitractin that has excellent activity against the virus of trachoma group, the same compounds

also exhibit antibacterial activity. 4-aryl dihydro pyrimidines e.g. nifedipine are the important

and the most studied class as calcium channel modulars. In 1975 their introduction in clinical

medicine for the treatment of cardiovascular diseases , some of the analogues were screened

as antitumor agents. Pyrimidine -5-carboxamide reported to possess anticarcinogenic activity.

Dihyro pyrimidine is a bioisoster of dihydro pyridine which shows very good calcium

channel blocking having amide linkage.

In recent scenario heterocyclic compounds play a major role in drug synthesis. In that

respect pyrimidine plays a significant role among other heterocyclics. From the literature

survey, in recent years 3, 4-dihydro pyrimidin-2(1H)-ones have attracted considerable interest

because of their therapeutic and pharmacological properties.

Reason for choosing the 3, 4 dihydro pyrimidones

Out of the five major bases in nucleic acids three are pyrimidine derivatives

which comprises of cytosine which is found in DNA and RNA, uracil in RNA

and thymine in DNA. Because of their involvement as bases in DNA and

RNA, they have become very important in the world of synthetic organic

chemistry. Aryl-substituted 3, 4-dihydro pyrimidin-2(1H)-ones and their

derivatives are an important class of substances in organic and medicinal

chemistry.

N

NH

ONH2

Cytosine

NH

NH

OOUracil

NH

NH

OO

CH3

Thymine

Figure 7. Bases in nucleic acid with pyrimidine nucleus

Several alkaloids containing the dihydro pyrimidine core unit have been

isolated from marine sources, which also exhibit interesting biological

properties. Most notably, among these are the batzelladine alkaloids, which

are found to be potent HIV gp-120-CD4 inhibitors.

Figure 8. Structure of Batzelladine - B

The scope of this pharmacophore has been further widened with their

identification of 4-(3-hydroxy phenyl)-2-thione derivative called monastrol as

a novel cell-permeable molecule for the development of new anticancer drugs.

Figure 9. Structure of Monastrol

Trimethoprim is a type of drug with a pyrimidine core which attacks the folic

acid metabolism of bacteria and is often used as antibacterial agents.

4-aryl-1, 4-dihydro pyridines (DHPs) of the nifedipine are the first most

potent group of calcium channel modulators available for the treatment of

cardiovascular diseases.

With the basis of the available literature and documentation of the existing in use

made me to choose 3, 4 dihydro pyrimidones.

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