Synthesis of 2, 3-disubstituted Quinazolin-4(3H)-ones-A Review

 

D. A. Patil*, P. O. Patil, P. K. Deshmukh, G. B. Patil, B. D. Shewale, D. D. Patil and S. G. Gattani

Department of Pharmaceutical Chemistry, H. R. Patel Institute of Pharmaceutical Education and Research, Karwand Naka, Shirpur, Dist- Dhule (Maharashtra), India- 425 405

*Corresponding Author E-mail: dilipapatil@gmail.com

 

 

ABSTRACT:

The present review covers a concise account of the synthesis of bioactive 2, 3-disubstituted quinazoline-4(3H)-ones and the recent developments in the area of versatile quinazolinones with a special emphasis on new synthetic routes and strategies.

 

KEYWORDS: Quinazoline-4(3H)-ones, benzoxazinones, heterocyclic.

 


INTRODUCTION:

Quinazolinones and related quinazolines are classes of fused heterocycles that are of considerable interest because of the diverse range of their biological properties, as antimalarial1, anticancer and anti-HIV agents2, antiviral3, antibacterial4, anticonvulsant5, antihypertensive6, antidiabetic7, antihistaminic8, and anti-inflammatory9.

 

The use of combinatorial synthesis, microwave-enhanced processes and new catalytic methodologies in the preparation of these heterocycles is a clear indication that significant advancement has been made in recent years. The syntheses of both quinazolinones and quinazolines can be classified into the following five categories, based on the substitution patterns of the ring system:

1.      2-Substituted-4(3H)-quinazolinones and quinazolines

2.      3-Substituted-4(3H)-quinazolinones

3.      4-Substituted-quinazolines

4.      2,3-Disubstituted-4(3H)-quinazolinones

5.      2,4-Disubstituted-4(3H)-quinazolinones and quinazolines

 

We describe the new and improved methods for the construction of the 4(3H)-quinazolinone and quinazoline skeletons, with a particular emphasis on 2, 3-disubstituted analogues. Within this class of quinazolinone nucleus subclasses are discussed as follows:

 

2, 3-Disubstituted-4(3H)-quinazolines:

1.      2,3-Disubstituted quinazolinones via benzoxazinones and benzoxazadiones

2.      Formation of 2,3-disubstituted quinazolinones from benzoxazepinediones

3.      Combinatorial approach to quinazolinones

4.      Formation of pyrrole-based quinazolinones from benzodiazepines

5.      Quinazolinones via copper-catalysed cyclisation

6.      Intramolecular coupling of azides to carbonyl groups, intramolecular dehydrative cyclization of diamides

7.      Quinazolinone derivatives via palladium-catalysed cyclocarbonylation

8.      Chemoselective lithiation of quinazolinone derivatives

9.      Reaction of polymer-bound anthranilamides with orthoformates

10.    Quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters under microwave irradiation, one-pot synthesis using silica sulfuric acid

11.    Preparation of 2,3-disubstituted quinazolinones using Appel’s salt

12.    Reaction of resin-bound aldehydes with anthranilamides

13.    Bis(imidoyl)chlorides for quinazoline formation

14.    Synthesis of fluorinated quinazolinones

15.    Approaches to luotonins and rutaecarpine

16.    Quinazolinone formation using 1-acetyl-1-methylhydrazine

17.    Fused Quinazolinones

 

2, 3-Disubstituted quinazolinones via benzoxazinones and benzoxazadiones:

Benzoxazinones and benzoxazadiones are common intermediates in the synthesis of 2,3-disubstituted quinazolinones. Parkanyi and Schmidt10 prepared 2,3-disubstitutedquinazolines from chloro-substituted anthranilic acids and acetic anhydride in a study similar to the work of Jiang et al11. The intermediate (4H)-3, 1-benzoxazinones such as 1 were reacted with amino substituted thiazoles 2a and 2b, 1,3,4-thiadiazole derivative 2b to afford the desired products 3 and 4 in moderate to good yields, Scheme 1, Table 1.

cheme 1.

 

Table 1. Synthesis of quinazolinones 3 and 4

Entry

Substituent

Yield (%)

1

5-Cl-3-(5-MT)

55

2

6-Cl-3-(5-MT)

42

3

7-Cl-3-(5-MT)

29

4

6,8-Cl2-3-(5-MT)

39

5

7-Cl-3-(4-MT)

47

6

6,8-Cl2-3-(4-MT)

51

7

7-Cl-3-(5-ETD)

52

8

6,8-Cl2-3-(5-ETD)

38

5-MT=5-methylthiazol-2-yl, 4-MT=4-methylthiazol-2-yl, 5-ETD=5- ethyl-1, 3, 4-thiadiazol-2-yl.

 

A similar approach was taken by Kumar et al. in their synthesis of the novel 2,3-disubstituted quinazolinone 6 from 1 and 5, Scheme 212.

 

Scheme 2

 

It is possible to introduce an acyclic N-substituent using this method as demonstrated by Zhou et al. for a range of sulfonamides 9 (88 in total) from 7 and 8 with a variety of substitution patterns, Scheme 3, Table 213. During the course of investigating this reaction, some open chain product 10 was isolated, Scheme 4. In order to test the hypothesis that this reaction proceeded via an open chain intermediate, equivalent amounts of 11 and benzenesulfonylhydrazide 12 were dissolved in anhydrous DMF.

 

 

The mixture was stirred at room temperature for 22 h, affording 10 and 5% of the cyclised product 13. Heating this mixture subsequently furnished 13 in 78% yield following chromatographic purification, supporting the idea of an acyclic intermediate.

 

Table-2 Synthesis of 3-sulfonamide-substituted quinazolines 9a

 

Entry

R2

R1 (% yield)b

Phenethyl

Bn

Ph

2-Thiophene

Methylene

1

4-CO2H-Ph

98

81

67

99

2

4-NHCOMe-Ph

99

94

58

99

3

4-OCF3-Ph

96

90

81

74

4

3,4-Di-Cl-Ph

83

85

40

29

5

4-CF3-Ph

90

92

87

45

6

4-CN-Ph

90

88

51

73

7

4-Cl-Ph

90

90

68

49

8

Bn

82

96

45

79

9

3-NO2-4-Cl-Ph

92

89

55

24

10

3-CO2H-Ph

99

98

98

83

11

5’-(N-Thiophen-2-yl-methyl-benzamide)

83

72

37

51

12

4-i-Pr-Ph

86

76

64

32

13

4-OMe-Ph

85

90

73

71

14

3,4-Di-F-Ph

92

89

98

75

15

2-Cl-Ph

95

70

60

80

16

3,4-Di-OMe-Ph

86

69

90

63

17

3,5-Di-Cl-Ph

95

92

53

50

18

4-F-Ph

95

98

99

78

19

4-NO2-Ph

95

81

99

97

20

4-t-Bu

92

84

44

50

21

2,4-Di-Cl-5-Me-Ph

57

17

26

< 5

22

2,4-Di-Cl-Ph

< 5

8

15

52

a All of the products <90% pure by ELSD were purified by reverse-phase HPLC in automated fashion using Waters MS-triggered purification system using ACN and H2O as eluting solvent.

b The yields are estimated by HPLC (ELSD) from LC-MS results of the reaction mixture before HPLC purification.

 

Xue et al. reported the optimisation of Grimmel’s conditions for generating C2,N3-disubstituted-4-quinazolinones14,15. Using Grimmel’s methodology, N-acetylanthranilic acids such as 14 are heated with anilines in toluene or xylene in the presence of dehydrating agents such as phosphorous trichloride, phosphorous oxychloride or thionyl chloride to yield 15, Scheme 5.

 

In Grimmel’s original paper, no trace of 16 was observed when N-acetoxyacetylanthranilic acid and aniline were refluxed together in the presence of 0.34 equiv of PCl3, Scheme 6.

 

 

 


Scheme 3


Scheme 4

 

Scheme 5


 

Scheme 6

 

When the same methodology was applied to o-chloroaniline 17 and carboxylic acid 18, however, a small amount of 19 (10%) was observed. Subsequent experimentation led to the isolation of 20, which was proposed as being a plausible intermediate in the formation of the quinazolinone product, Scheme 7. By changing both the solvent and the temperature used, yields from 87 to 98% for a range of quinazolinones were obtained in polar aprotic solvents.

 

 

Virgil and Dai reported the synthesis of 2-hetero-substituted atropisomeric quinazolinone phosphine ligands in good yields16. The synthesis of the 2-unsubstituted ligand was initiated by the formation of (4H)-3, 1-benzoxazin-4-one 21 via the condensation of anthranilic acid 22 with trimethyl orthoester, Scheme 8.

Scheme 7

 

Scheme 8


After removal of the excess orthoester, the crude product was mixed with aminophosphine in toluene and subsequently heated to reflux for 6 h to afford the quinazolinone 23 in 88% yield, Scheme 9.

 

Scheme 9

 

By direct lithiation of the 2-unsubstituted quinazolinone system 23 it was possible to carry out a range of electrophilic substitutions, Scheme 10.

 

Scheme 10

 


Electrophiles such as chlorodiphenylphosphine, solid sulfur and dimethyl disulfide were added at -780C to furnish a new series of quinazolinone-based ligands. This concise one-pot synthesis allows efficient access to a new class of P–S and P–P chelate atropisomeric ligands 24. An earlier procedure implemented by Virgil and co-workers focused on the synthesis of monodentate atropisomeric ligands for asymmetric catalysis. This was based on the reaction of phosphoanilines 25 with N-acetyl anthranillic acid 26 and employed benzenesulfonyl chloride as the coupling agent, Scheme 1117.

 

Both of these methods allow access to the desired quinazolinones in good yields and the method is amenable to efficient scale up18. Dandia et al. reported the synthesis of fluorinated 2,3-disubstituted quinazoline-4(3H)ones 29 under microwave conditions19.

The intermediate benzoxazin-4-one 27 was synthesised in situ by reacting the anthranilamide derivative 28 with acetic anhydride, Scheme 12 meta- and para-substituted anilines gave 2,3-disubstituted quinazolinone products 29a in good yield, whereas ortho-substituted anilines produced only 29b.  Proceeding via a benzoxazine does not, however, guarantee that a 2, 3-disubstituted quinazolinone will be obtained. De Fatima Pereira et al. disclosed that efforts to produce 30 via 31 failed, Scheme 1320. In spite of these limitations, it is clear from the numerous examples cited that this is an important intermediate in the synthesis of 2, 3-disubstituted quinazolinones and provides access to unusual substitution patterns in the final products.


 

Scheme 11


 

Scheme 12


 

Scheme 13

 

Saroj Kumari et al. reported the synthesis of (3Z)-1H-indole-2,3-dione-3-{[3-(4-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]hydrazone} 34 from 2,3-dioxoindole and 2-hydrazino-3-(4-methylphenyl)-quinazolin-4(3H)-one, Scheme 14. Commencing from anthranilic acid and 4-methylphenylisothiocynate to produce 3-(4-methylphenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one 32 in excellent yield 85%.

 

The thioxoquinazolinone and anhydrous hydrazine in methanol produced 2-hydrazino-3-(4-methylphenyl)-quinazolin-4(3H)-one 33. Followed by treatment with 2,3-dioxoindole gives (3Z)-1H-indole-2,3-dione-3-{[3-(4-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]hydrazone}3421.

 

Synthesis of 3-(4-methylphenyl)-2-[2-(2-oxo-2, 3-dihydro-1H-indol-3-yl)hydrazino]-quinazolin-4(3H)-one  34.

Ji-Feng Liu recently described the efficient and concise total syntheses of fumiquinazolines, mackinazolinone 35, isaindigotone 36, and quinazolinobenzodiazepine natural products. This methodology additionally enabled to rapidly access libraries of related natural product derivatives. The library synthesis was performed on a microwave station integrated into a solution-phase high-throughput automated synthesis platform.

 


Scheme 14


 

Reaction of anthranilic acids 37 with N-Boc amino acid 38 in the presence of P(OPh)3 in pyridine at 220°C for 10 min under microwave irradiation, followed by addition of the benzaldehydes 39 microwave irradiation at 230°C for 12 min yielded compounds 4022. Scheme 15.

 

William J. Watkins reported the synthesis of 3-(N′-methyl-piperazinyl)-quinazolinones, Scheme 16. The synthesis of all variants of the quinazolinone core started from the requisite anthranilic acid23 Table 3.

 

 

Scheme 15- Synthesis of the mackinazolinone natural product-templated library

 

Scheme 16- Racemic synthesis of 3-(N′-methyl-piperazinyl)-quinazolinones.


 

 

S. Wang et al described syntheses of the analogues derived from lead molecule 44 when anthranilic acids 45 were reacted with acid chlorides 50 in pyridine at 0°C benzooxazinones 46 were obtained as crystalline products, scheme 17. The subsequent reflux with amines 51 and catalytic amount of pTSA in toluene gave a mixture of quinazolinones 47 and uncyclized diamides 48, which were converted to products 47 by heating in acetic acid and concentrated sulfuric acid (9:1) at 100°C for 15 min24

 

 

In Scheme18, anthranilic amides 52 were converted into the corresponding iminophosphorane derivatives 53 with triphenyl phosphine/hexachloroethane/triethyl amine.25 The subsequent aza-Wittig reactions and heterocyclizations with acid chlorides 50 in refluxing toluene gave the quinazolinones 47 in moderate yields. The substitutions are given in the table 4.

 

Table 3. Variants of the 3-chlorophenyl urea moiety in 41, Variants of the 2,4-dimethoxyphenyl moiety in 42 and Variants of the quinazolinone core in 43.

Variants of the 3-chlorophenyl urea moiety (link) in 41

Variants of the 2,4- di-methoxyphenyl moiety in 42

Variants of the quinazolinone

core in 43

Link

R

R

R

CONH

(3Cl)Ph

(2,4-diOMe)Ph

H

H

--

Me

5-F

CONH

iPr

Ph

6-F

CONH

(4-Cl)Ph

(2-OMe)Ph

7-F

CONH

(2-Cl)Ph

(4-OMe)Ph

6,7-diF

CONH

Ph

(3-OMe)Ph

6-Cl

CONH

(4-F)Ph

(2,4,6-triOMe)Ph

7-Cl

CONH

(4-Me)Ph

(3,4-diOMe)Ph

6-Me

CONH

(4-OMe)Ph

(3,4,5-triOMe)Ph

6-OMe

CONH

(3-CN)Ph

(2,4-diF)Ph

8-OMe

CONH

(3-Cl)-6-Pyridazinyl

(2,4-diMe)Ph

6-OH

CONH

2-Benzthiazolyl

(2,4-diOCH2cPr)Pha

6-OCOCH2CH3

CO2

(4-Cl)Ph

3-(2,6-diOMe)pyridyl

6-OCH2CONH2

SO2

(4-Cl)Ph

 

6-NHSO2CH3

CONHSO2

(4-Cl)Ph

 

6-NHCOCH3

CO

(4-Cl)Ph

 

7-CN

CO

(2-Cl)Ph

 

7-CO2Me

 

 

 

7-CO2H

 

 

 

7-Aza

 

 

 

8-Aza

a cPr = cyclopropyl.


Scheme 17.

Reagents: (a) R1COCl, TEA or Pyr, DCM, 00C; (b) R2NH2, Tol., pTSA; (c) AcOH/H2SO4 (9:1), 1000C; (d) SnCl2.2H2O, EtOH, reflux; (e) R’COCl, TEA, CHCl3.


 

Scheme 18. Reagents: (a) PPh3, Cl3CCCl3, benzene, TEA, reflux; (b) R1COCl, TEA, tol.

 

Gaurav Grover et al. synthesised some nalidixic acid derivatives carrying the biodynamic heterocyclic systems as quinazolones at position-3.26

 

A. Gursoy et al., synthesized series of 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)-mercaptoacetyl]-hydrazono]-1H-2-indolinones 57.27

 

Table 4. 3-substituted compounds 54, 2-(substituted)-phenyl compounds 55, Benzo-substituted quinazolinone Compounds 56

 

Variants in structure 54,

R =

Variants in structure 55, R=

Variants in structure 56, R=

CH2-N-Tetrahydroisoquinoline

4-N(CH3)2

H

n-Pentyl

H

5-Cl

Cyclohexyl

3-N(CH3)2

6-Cl

Ph

4-iPr

7-Cl

CH2-4-pyridyl

4-N(Et)2

8-Cl

CH2-N-(6,7-dimethoxy)-Tetrahydroisoquinoline

3-nPr

8-CH3

CH2-N-Piperazine-N-Bn

3,4-(OCH2O)

8-OCH3

CH2N(CH3)–(CH2)2–(3,4-dimethoxy-phenyl)

2-OH nda

7-NO2

CH2-N-Piperazine-N-(3,4,5-trimethoxy)-benzoyl

4-Ph

7-NH2

CH2-N-Piperazine-N-2-pyrimidine

 

6-NO­2

 

Anette Witt and Jan Bergman reported the halosubstituted vinylquinazolinones 58b and 58c and The vinylquinazolinones 58a and 59 in overall yields of 66% from anthranilamide and 3-chloropropionyl chloride28.

              

Fuks has given an example, where 60 (R1=H, R2 = i-Pr) was prepared in a low yield by reacting the nitrilium salt 8 with methyl anthranilate (structures 60 and 61)29. Skibo et al. 1992, 1993 has reported the preparation of 5,8-dihydroxy-2-vinyl-3H-quinazolin-4-one30.

 


Scheme 19

Scheme 20.

Reagents and conditions: (a) (R1 = Me): acetic anhydride, MW (200 W), 130°C, 10 min; (R1 = Et): propionic anhydride, MW (200 W), 160°C, 10 min; (b) aliphatic amine (R2–NH2) (2 equiv), CH2Cl2, rt, 10–40 min; (c) formamide, MW (200 W), 170°C, 10 min.

 


Alagarsamy et al., reported the synthesis of 2-methyl-3-(substituted methylamino)-(3H)-quinazolin-4-ones 62 by condensing the active hudrogen atom of the amino group of 3-amino-(3H)-quinazolinone-4-one with formaldehyde and appropriate amines31.

 

Ji-Feng Liu reported the microwave promoted one-pot, two-step synthesis of 2,3-disubstituted 3H-quinazolin-4-ones 69. The synthesis begins with the condensation of an anthranilic acid 63, with either an acylchloride 64 or a carboxylic acid 65 followed by dehydration to form the intermediate benzoxazinones 66. Subsequent addition of an amine 67  initially provides the transient amidine salt species 68 which rapidly cyclizes to yield the desired 2,3-disubstituted 3H-quinazolin-4-ones 6932, scheme 19, Table 5.

 

Optimized one-pot microwave promoted synthesis of 2,3-disubstituted 3H-quinazolin-4-ones 69; Optimized conditions: (1) For R1COCl (1.5 equiv), P(PhO)3 (1.2 equiv), pyridine (2.0 mL), 25°C, 60 min; or for R1CO2H (1.0 equiv), P(PhO)3 (1.2 equiv), pyridine (1.0 mL), Microwave, 150°C, 10 min; (2) R2NH2 (1.5 equiv) when R1COCl used, R2NH2 (1.0 equiv) when R1CO2H used, microwave, 250°C, 3–10 min.

 

Kostakis reported an efficient methodology for the preparation of a series of 2,3-disubstituted-quinazolin-4(3H)-ones via a three step reaction from anthranilic acid33.

 

Table 5. Chemistry and scope of microwave promoted synthesis of 2, 3-disubstituted 3H-quinazolin-4-ones 69

Entry

R

R1

R2

Yielda of 1b (%)

1

H

Phc

Ph

100 (88)

2

H

Phc

 

90 (60)

3

H

Phc

Bn

95 (80)

4

H

Phc

 

100 (85)

5

H

Phc

 

95 (66)

6

H

Bnd

 

100 (62)

7

H

 

 

94 (46)

8

H

 

 

100 (53)

9

H

 

 

95 (50)

10

H

Etd

Bn

100 (64)

11

5-Me

Med

 

100 (59)

12

4-Cl

 

Bn

100 (66)

13

4,5-(OMe)2

4-OMe-Bnd

 

100 (64)

14

Note e

Phc

Bn

95 (68)

15

H

Med

 

95 (65)

aThe yields are determined by HPLC (ELSD) from LC–MS results of the reaction mixture. In parentheses, isolated yields by preparative TLC or flash column chromatography. bCharacterized by 1H NMR, 13C NMR, and HRMS. cR1COCl used: 25°C/60 min. dR1CO2H used: Microwave 150°C/10 min. e2-Aminonicotinic acid used.

 

The synthesis of the desired quinazolin-4(3H)-ones 75a-e and 76a-e was performed in three steps starting from anthranilic acid 70 and using 3,1-benzoxazinones 71 and 72 as intermediates scheme 20. The first synthetic step involved the condensation of anthranilic acid 70 with acetic or propionic anhydride to afford the desired benzoxazinones (71 and 72, respectively) in quantitative yields. Intermediates 71 and 72 were then totally converted into 73a-e and 74a-e through treatment with an excess of the appropriate aliphatic amine. Finally, the obtained diamides were subjected to microwave-assisted cyclocondensation to give the desired quinazolinones 75a-e and 76a-e in good yields (Table 6).

 

Table 6 Synthesis of 2,3-disubstituted-quinazolin-4(3H)-one 75a-e, 76a-e   from anthranilic acid 70.

Entry

R1

R2

Yielda (%)

1

Me

Me

84

2

Me

n-Bu

75

3

Me

 

77

4

Me

 

83

5

Me

 

77

6

Et

Me

87

7

Et

n-Bu

74

8

Et

 

85

9

Et

 

86

10

Et

 

87

aOverall yield from anthranilic acid.

 

Nouira et al reported generation of ammonia via thermal decomposition of formamide under microwave conditions to provide an efficient tool for the synthesis of nitrogen-containing heterocycles as quinazolin-4-ones, which are known as building blocks for molecules with pharmaceutical interest34. Synthesis of 2,3-disubstituted quinazolin-4(3H)-ones 50 was performed in three steps starting from anthranilic acid and using 3,1-benzoxazinones as intermediates. In these compounds, an alkyl group was inserted into the quinazolinone ring in position 2 by nucleophilic attack of an appropriate aliphatic amine (R-NH2) and a microwave-assisted cyclocondensation of the intermediate diamides.

 

Kashaw et al., reported synthesis of several new 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea, scheme 2135. Synthesis of 2-ethylbenzoxazin-4-one 79, 2-phenyl-benzoxazin-4-one 77 and substituted aryl semicarbazides 78a-l were synthesized by the reported methods. Synthesis of the target compounds was carried out according to the scheme 1. Different substituted semicarbazides 78a-l were refluxed in the presence of glacial acetic acid with 2-ethylbenzoxazone 79 and 2-phenyl benzoxazin-4-one 77 to yield 80a-l and 81a-l, respectively (Yield 45-78 %).

 


 

Scheme 21. 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea

 


 

V. Alagarsamy reported the 2-methyl-3-(substituted methylamino)-(3H)-quianzolin-4-ones 82a-j by condensing the active hydrogen atom of the amino group of 3-amino-2-methyl (3H)-quinazolin-4-one with formaldehyde and appropriate amines, scheme 2236. The synthesis of  82a achieved by adding a mixture of formalin (37-41%; 1 ml) and dimethylamine drop by drop with stirring to a slurry of 3-amino-2-methyl-(3H)-quinazolin-4-one in dimethlformamide.

 

Scheme 22 Synthesis of 2-methyl-3-(substituted methylamino)-(3H)-quianzolin-4-ones 82a-j R1/R2= dimethyl, diethyl, pyrrolidinyl, morpholinyl, piperazinyl, phenyl, 4-carboxyphenyl, 4-sulphonamido phenyl, pyridi-2-yl, benzimidazole-1-yl.

 

N. Sati, reported 2-phenyl-3-(substituted phenyl)-3H-quinazolin-4-ones 83a-f from anthranillic acid scheme 2337.

 

Scheme 23 Synthesis 2-phenyl-3-(substituted phenyl)-3H-quinazolin-4-ones 83a-f; R2 = H, Cl, CH3, OCH3; R4= H, F, CH3; R6= H, CH3.

 

1.      Formation of 2,3-disubstituted quinazolinones from benzoxazepinediones:

Uskokovic et al. reported the synthesis of 2-(a-hydroxyalkyl)- 3-N-methylquinazolinones 86 from 4,1-benzoxazepine-2,5(1H,3H)-diones 8538. Commencing with anthranilic acid, amidation proceeds in excellent yield, Scheme 24. Ring closure of 84 to form the benzoxazepines was achieved by heating to reflux in DMF for 3 h, giving 85 in acceptable yield. The formation of 86 was achieved in methanolic solution in the presence of methylamine over 1 week.

 

2.      Combinatorial approach to quinazolinones:

Houghten et al. developed a novel, traceless and chemoselective approach for the solid-phase synthesis of 2-arylamino-substituted quinazolinones with the possibility of manipulation at three positions39. Starting from the p-methyl benzhydryl amine (MBHA) resin 87, a specific o-nitrobenzoic acid was attached and the aromatic nitro group was then reduced with tin(II) chloride to furnish the required o-aniline 88, Scheme 25. The resin was dried and subsequently reacted with an appropriate aryl isothiocyanate and the resin-bound thiourea 89 was reacted with Mukaiyama’s reagent (2-chloro-1-methylpyridinium iodide). A primary amine was added at room temperature to generate the corresponding guanidine 90 and the desired 2-amino-substituted quinazoline was obtained via an intramolecular cyclisation. This was followed by cleavage from the resin using hydrofluoric acid at 0-8°C for 1.5 h to give the product quinazoline 91 in good yield and purity, Table 7.

 

Table 7 Combinatorial production of quinazolines 91

Entry

R1

R2

R3

Yield of

91 (%)a

1

H

2-Cl, 4-NO2

i-Bu

86

2

H

4-NO2

(Me)2CHCH2CH2CH2

89

3

H

2,3-Cl

i-Bu

83

4

H

3-Cl

i-Bu

91

5

H

4-CN

i-Bu

88

6

H

H

i-Bu

86

7

H

4-NO2

PhCH2CH2CH2

85

8

H

4-NO2

Me(CH2)4CH2

88

9

5-MeO

4-NO2

(Me)2CHCH2CH2CH2

85

10

5-Pyridyl

3,5-Cl

Me(CH2)2CH2

86

11

5-Pyridyl

4-NO2

Me(CH2)2CH2

88

 

 aBased on weight of crude material (relative to the initial loading of the resin).

 


 

Scheme 24


Scheme 25

 


This method demonstrates a traceless approach for the parallel solid-phase synthesis of o-arylamino-substituted quinazolines from common materials such as 2-nitrobenzoic acid derivatives (R1), aryl isocyanates (R2) and amines (R3). The literature on solid-phase approaches to quinazolines and quinazolinones has recently been reviewed by Vogtle and Marzinzik40.

 

3.                Formation of pyrrole-based quinazolinones from benzodiazepines:

The medicinal research of Fabis et al. showed that the aromatic system of pyrrolo[2,1-c][1,4]benzodiazepine was reactive towards nucleophiles, leading to the formation of quinazolines as rearrangement products41. Heating the 2-hydroxypyrrolo[2,1-c][1,4]benzodiazepine with thionyl chloride 92 in the presence of pyridine gave the 11-chloropyrrolo[2,1-c][1,4]benzodiazepine 93 in 70% yield, Scheme 26. This represents a straightforward method for the synthesis of aromatic pyrrolo[2,1-c][1,4]benzodiazepines. It became apparent that the double reactivity of such compounds at the carbonylpyrrole bond and at the chloroimine moiety would be useful in accessing the quinazolinone skeleton. This was exemplified by the addition of hydrazine to furnish the desired 3-amino-2-(1Hpyrrol-2-yl)-4(3H)-quinazolinone 94 in a respectable 60% yield.

Scheme 26

 

4.      Quinazolinones via copper-catalysed cyclisation:

Kundu and Chaudhuri developed a novel copper-catalysed heteroannulation to (E)-2-(2-arylvinyl)-quinazolinones from alkynes42. A series of 2-[N-alkyl(benzyl)-N-(prop-20-ynyl] aminobenzamides 95 reacted with aryl iodides under palladium–copper catalysis to yield the disubstituted alkynes 96.

 

The alkynes subsequently underwent a highly regio- and stereoselective cyclisation in the presence of CuI, K2CO3 and n-Bu4NBr in acetonitrile to furnish the required quinazolinones in good yields, Scheme 27, Table 8. The conversion of the alkynyl-aminobenzamides into the disubstituted alkynes occurred via a Sonogashira–Hagihara coupling followed by a rearrangement to the allene intermediates 97. The amide nitrogen partakes in nucleophillic attack on the terminal carbon of the allene with concomitant ring closure to give the substituted quinazoline derivatives 98 with predominant E-stereochemistry at the vinylic group.

 

This is the first reported synthesis of quinazolinones employing a copper-catalysed cyclisation. The method is very mild, requires inexpensive starting materials and is experimentally undemanding.

 

Table 8 Synthesis of Quinazolinones 98 by copper-catalyzed cyclization

Entry

R

Ar

1

CH3

2-MeC6H4

2

CH3

2-Thienyl

3

CH3

2,4-Dimethoxypyrimidin-5-yl

4

CH3

2-MeCO2C6H4

5

Bn

2-MeC6H4

6

Bn

2-Thienyl

7

Bn

2,4-Dimethoxypyrimidin-5-yl

8

Bn

2-MeCO2C6H4

 

5.                Intramolecular coupling of azides to carbonyl groups, intramolecular dehydrative cyclization of diamides

A mild and efficient route for the synthesis of fused [2,1-b]quinazolinones was reported by Kamal and co-workers43. The procedure employs an intermolecular azido-reductive cyclisation in the preparation of the pyrrolo[2,1-b]quinazolinone ring system 99, Scheme 28, This was exploited in the synthesis of deoxyvasicinone, a precursor for vasicinone, a known bronchodilator by Amin et al44.

 

The FeCl3/NaI combination had not previously been investigated for the reduction of the azide functionality and the

 

role of NaI could be attributed to the in situ formation of FeI3. In addition, the use of excess NaI appears to be crucial for high conversions. This new reductive cyclisation method affords an alternative route towards the preparation of these pharmacologically important fused quinazolinones 99 in high yields (85–97%). The synthesis of optically active l-vasicinone, a known pyrrolo[2,1-b]-quinazolinone alkaloid, was undertaken by Eguchi et al. employing the intramolecular aza-Wittig reaction as the key step in the construction of the quinazolinone ring skeleton, Scheme 2945.

 


Scheme 27

 

 


Scheme 28

 

Scheme 29

 


 

The synthesis of l-vasicinone was initiated by protection of the chiral synthon, (3S)-3-hydroxy-g-lactam with tertbutyldimethylsilyl chloride, followed by condensation with o-azidobenzoyl chloride 100 using sodium hydride in tetrahydrofuran. The intermediate 101 was treated with trin-butylphosphine, which, in turn, initiated the tandem Staudinger-intramolecular aza-Wittig reaction, furnishing o-tert-butyldimethylsilyl vasicinone 102 in 76% yield.  Finally, deprotection of the silyl ether by tetra-n-butylammonium fluoride (TBAF) enabled the preparation of l-vasicinone in 52% overall yield with a 97% ee.

 

Recently Hernandez et al. reported the use of an Eguchi aza-Wittig reaction to fashion the 2, 3-disubstituted quinazolinone skeleton in the course of a synthesis of analogues of N-acetylardeemin, a multidrug resistance reversal agent46.

 

Kshirsagar reported a simple and efficient general approach to various quinazolinone scaffolds, including peptidomimetic examples, has been demonstrated by employing hexamethyldisilazane (HMDS) /I2 for the intramolecular dehydrative cyclization of diamides47. They reported a new, facile and general approach to natural and unnatural quinazolinones scheme 30. Anthranilamides 103 were prepared in very good yields from the reactions of isatoic anhydride/sulfinamide anhydride with a variety of primary amines. Intermediates 105 were prepared by condensing anthranilamides 103 with the appropriate acid chlorides/carboxylic acids 104 in 82–98% yield (Scheme 30, Table 9, entries 1–11). Treatment of 105 with HMDS/ZnCl2 in benzene solution under reflux (Vorbruggen’s protocol)48 11 furnished the desired products 106 in ≈100% yields. The protecting groups –Boc, -Fmoc and –Cbz tolerated the present reaction conditions and in addition, not observed any racemization.

 

Table 9 Conversion of anthranilamides 103 to diamides 105 and quinazolinones 106

Entry

-R

-R’

X

Yield %

1

 

-CH2CH3

Cl

93

2

 

 

Cl

95

3

 

 

Cl

86

4

 

 

OH

70

5

 

-CH2CH3

Cl

97

6

 

 

Cl

96

7

 

 

Cl

90

8

 

-CH2NHFmoc

Cl

75

9

 

-CH2NHCbz

OH

65

10

 

 

Cl

75

11

 

 

Cl

65


Scheme 30. Synthesis of unnatural quinazolinones and precursors of natural quinazolinones (i) TEA, DCM / EDCI, HOBT,  rt, 8 h; (ii) HMDS (1.5), I2 (0.5), DCM, rt, 30 min-3h.

 

cheme 31

 

Scheme 32


 

6.      Quinazolinone derivatives via palladium-catalysed cyclocarbonylation:

Larksarp and Alper developed a palladium acetate/ diphenylphosphinoferrocene (dppf) catalyst system for the cyclocarbonylation of o-iodoanilines 107 with heterocumulenes 108 to afford the corresponding 4(3H)-quinazolinone derivatives 109, Scheme 3149. Carbodiimides and ketenimines were employed in this convenient synthesis and the reactions were conducted at 100°C for 24 h under carbon monoxide pressure, Table 10.

 

Table 10. Synthesis of 2-amino-4(3H)-quinazolinones 109 from iodoanilines 107 and carbodiimides 108

 

Entry

R

R1

1

H

4-ClC6H4

2

H

4-BrC6H4

3

H

Cy

4

H

Ph

5

H

4-MeC6H4

 

 

2-Amino-4(3H)-quinazolinones were accessed in moderate to good yields by employing carbodiimide 108 under the conditions described. The reaction was found to tolerate both nitrile and hydroxyl functional groups on the o-iodoanilines, only starting material was however, recovered when carbodiimides bearing electron-donating substituents were used.

 

7.      Chemoselective lithiation of quinazolinone derivatives

Smith et al. reported the preparation of 3-(acylamino)-2-unsubstituted and 3-amino-2-substituted quinazolinone systems 110 and their subsequent lithiation, Scheme 3250.

 

The required 3-(pivaloylamino)- and 3-(acetylamino)-4(3H)-quinazolinones 110a and 110b were prepared as outlined in Scheme 32. For example, the former compound was prepared in 85% yield from the reaction of pivaloyl chloride with 3-amino-quinazolinone. Subsequent treatment with alkyllithium reagents promoted nucleophilic attack at the imine bond, giving the corresponding 1,2-addition product 111, rather than lithiation at the 2-position, Scheme 33, Route A.


 

Scheme 33

 

Scheme 34

 

Scheme 35-Route A


 

The reactions were complete within a 5 min period and very good yields of the addition products were achieved, Route A. It was later discovered that chemoselective lithiation at the 2-position of 3-(pivaloylamino)- and 3-(acylamino)-4(3H)-quinazolinones 110a and 110b was possible using lithium diisopropylamide at low temperature to furnish a range of 2-substituted products 112, Scheme 33, Route B.

 

This direct lithiation is a facile, practical and regioselective process, enabling the synthesis of a range of derivatives including those that are not easily accessed by other routes.

 

The ease of removal of the acylamino group affords the 3-amino analogues 113 under basic or acidic conditions, Scheme 34.

 

A subsequent discovery showed that 3-amino-2-methyl-4(3H)-quinazolinones 114 could be lithiated readily using 2.2 equiv of n-butyllithium at low temperature in THF and then quenched by a series of electrophiles in high yield51. Interestingly, attack by the n-BuLi at the carbonyl group or the imine functionality of the quinazolinone ring did not occur, Scheme 35, Route A.

 


 

Scheme 35-Route B

 


Based on the success observed using alkyllithiums, the methodology was transferred to the 3-amino-2-ethyl-4(3H)-quinazolinones 115, although only low yields of the desired products were obtained. Increased yields were achieved, however, by the use of lithium diisopropylamide at low temperature, Scheme 36, Route B. These simple procedures provide aminoquinazolinone derivatives that were only previously available with difficulty. This new approach obviates the need for protecting groups and allows direct access to quinazolinones bearing the amino functionality.

 

8.      Reaction of polymer-bound anthranilamides with orthoformates:

Makino et al. synthesised a series of quinazolinones 116 by cyclocondensation of anthranilamides on solid supports with a variety of orthoformates, Scheme 3752. The reactions proceeded smoothly under mildly acidic conditions and the products obtained exhibited excellent purity. In this procedure, implemented by Makino, a surface grafted polymer, Synphasee Lanterns, with a long-chain hydroxymethyl phenoxy linker was employed. Since the reaction with carboxylic acids did not proceed smoothly on the solid phase, orthoformates were applied as carboxylic acid equivalents in the cyclocondensation. The reaction proceeded well with acetic acid and N-methyl-pyrrolidone (NMP). This strategy worked for both alkyl and aryl orthoformates with yields of around 70% based on theoretical loading weights of the target molecules.

 

Scheme 37

 

An advantageous feature of this method is that molecules with functional groups such as alkenes can be synthesized without problems under the mildly acidic conditions employed. Although the route is limited by the commercial availability of the orthoformates, it is superior to the solid phase synthesis reported by Zhang et al53. In Zhang’s procedure, reagents with a lower oxidation state than orthoformates were employed. An oxidation step was, however, required and the products

 

obtained were not of high purity, Scheme 38. This method is effective for the preparation of 2-alkyl- and 2-aryl-3-substituted-quinazolinones 117, but it is not applicable to the synthesis of molecules that are susceptible to oxidation.

 

Scheme 38

 

9.      Quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters under microwave irradiation, one-pot synthesis using silica sulfuric acid:

 

Hassan Hazarkhani et al., designed and synthesized 3-(2-benzimidazolyl)-2-alkyl-4(3H)-quinazolinones 119 as new heterocyclic compounds that contain both benzimidazole and quinazolinone moieties in their structures54. To prepare new polyheterocyclic systems bearing two or three different heterocyclic nuclei, isatoic anhydride has been used55. When a mixture of isatoic anhydride and 2-aminobenzimidazole in DMAC was irradiated with microwave (300 W power) in the presence of a catalytic amount of p-toluenesulfonic acid, the reaction was almost completed within 2 min. Work-up of the reaction mixture shows that 2-amino-N-(1-H-benzimidazol-2-yl) benzamide 118 was prepared in 70% yield after recrystallization from 95% ethanol Scheme 39.


 

Scheme 39


 

Scheme 40

 

Scheme 41

 


Interestingly, it was found that this reaction is highly chemoselective in the preparation of amide 118. This new amide has three nucleophilic sites that can be condensed with different electrophilic species for preparation of a wide variety of quinazolinone based targets. Herein, we wish to report the synthesis of 3-(2-benzimida-zolyl)-2-alkyl-4-(3H)-quinazolinones 119 through the reaction of 118 with a set of orthoesters under microwave irradiation. They have carried out the reaction of 2-amino-N-benzimidazolyl benzamide 118 with triethylorthoformate under microwave irradiations to afford pure 3-benzimidazolyl-4(3H)-quinazolinone 119 in 94% yield Scheme 40.

 

Table 11. Synthesis of 2,3-disubstituted quinazolin-4(3H)-ones 122 by the reaction of isatoic anhydride, primary amines, and different orthoesters under solvent free conditions.

Entry

R

R’

% Yielda

1

CH3

4-ClC6H4

78

2

CH3

4-CH3C6H4

80

3

CH3

C6H5

81

4

CH3

4-CH3CH2C6H4

80

5

CH3

C6H5CH2

85

6

CH3

C6H5CH2CH2

83

7

CH3

CH3CH2

87

8

CH3

2-CH3C6H4

81

9

CH3CH2

CH3CH2

86

10

CH3CH2

4-CH3C6H4

81

11

CH3CH2

4-BrC6H4

78

12

CH3CH2CH2

4-CH3C6H4

84

13

CH3CH2CH2

C6H5CH2CH2

81

14

CH3CH2CH2

4-BrC6H4

77

15

CH3CH2CH2

C6H5

80

16

CH3CH2CH2

4-CH3C6H4

79

17

CH3CH2CH2CH2

C6H5CH2CH2

79

18

C6H5

C6H5

79

19

C6H5

4-CH3C6H4

79

20

C6H5

4-ClC6H4

75

21

C6H5

C6H5CH2CH2

80

 a Isolated yield.

 

Salehi P. et al. reported quinazolin-4(3H)-one derivatives 122 synthesized via a one-pot, three component reaction of isatoic anhydride 120 and an orthoester 121 with ammonium acetate or a primary amine catalyzed by silica sulfuric acid under solvent-free conditions.56 This is the first report on the synthesis of 2-substituted quinazolin-4(3H)-ones by this procedure. The synthesis of 2, 3-disubstituted quinazolin-4(3H)-ones was another goal of this study. When isatoic anhydride, a primary amine, and an orthoester, were mixed in the presence of catalytic amounts of silica sulfuric acid under solvent-free conditions, the expected products were obtained satisfactorily, scheme 41. The results are summarized in Table 11.

 

Heravi, et al., reported a new synthesis of 4(3H)-quinazolinone from the reaction of 2-amino-benzamide and acylchlorides in the presence of catalytic amounts of silica-supported Preyssler nano particles as green, reusable and efficient catalyst under ultra sonic irradiation.57

 

10.              Preparation of 2,3-disubstituted quinazolinones using Appel’s salt

Christopher et al. developed a facile synthesis of 3-substituted 2-cyano-4(3H)-quinazolinones 125 by the reaction of primary alkylamines with intermediate 124.58 The latter was prepared in 50% yield by the reaction of methyl anthranilate 50 with 4,5-dichloro-1,2,3-dithiazolium chloride (Appel’s salt) 123 in the presence of pyridine, Scheme 42.

 

Scheme 42

The 3-alkyl-2-cyano-4(3H)-quinazolinones 125 were furnished in moderate to good yields, Table 22. The cyano group of the 3-methyl-2-cyano-4(3H)-quinazolinone 125 (RZMe) can be readily displaced by various nucleophiles to give the corresponding 2-substituted analogues in good to excellent yields. This allows a rapid and efficient synthesis of new quinazoline systems. de Fatima Pereira reported the synthesis of novel 1-imino-2,3-dihydro-1H-pyrazino[2,1,-b]quinazoline-5-ones in acceptable yield in a two-step process, Scheme 70.20 Commencing with a methyl anthranilate, Appel’s salt condenses with the amino group. In a second condensation step, 1,2-diaminoethane condenses to give either 126 or 127.

 

11.    Reaction of resin-bound aldehydes with anthranilamides

In a solid-phase synthesis of quinazolinones by Zhang et al., polymer-supported anthranilamide precursors and aldehydes were combined under acidic conditions to furnish the quinazolinone 128 and 1,2-dihydro-quinazolinone, 129 skeletons, Scheme 43.53

 

Using the standard Fmoc-chemistry of solid-phase peptide synthesis (SPPS), the resin-bound amino acid derivative was sequentially condensed with anthranilic acid and Fmoc-protected amino acid chloride to produce the corresponding tripeptide on solid support (the Wang resin, in this study).

Previously, this tripeptide precursor was intramolecularly dehydrated with Ph3P/I2/DIEA, subsequently deprotected and cyclized with concomitant detachment from the solid support to finally afford the desired product. This multi-step procedure, however, suffered from the use of a large excess of reagents (5–10 equiv) and very long reaction time, especially when two non-Gly amino acids were involved as parts of the tripeptide substrate. In this paper, the author reported that aforementioned reaction steps could be conveniently furnished in one single step using Lewis acids such as zinc triflate.

 

Subsequent dehydrogenation was effected using potassium permanganate. The desired products were obtained in acceptable yields and purities after cleavage with trifluoroacetic acid and additional diversity at the 3-position was possible by employing an amino acid-derivatised polymer support. An advantage of this approach is that the anthranilamide derivatised Wang resins 130 could be derived from either nitrobenzoic acids or isatoic anhydrides, allowing a series of aromatic substitution patterns to be accessed.

 

Chung Tseng reported the direct one-pot double cyclodehydration of linear tripeptides to the total synthesis of pyrazino[2,1-b]quinazoline-3,6-diones scheme 44, 131a-l on solid support using zinc triflate with good overall yields in short reaction time.59 These syntheses of the pyrazino [2,1-b]quinazoline-3,6-diones were conveniently achieved in only three steps, starting from the amino acid-bound Wang resin.

 

12.    Bis(imidoyl)chlorides for quinazoline formation:

The reaction of anthranilic acids 132 with oxalic acidbis(imidoyl) chlorides 133 to prepare quinazolinones 134 was detailed by Langer and Doring60. From their studies, moderate to good yields were achieved with reaction times of 3 days at 60°C, Scheme 45.

 


 

Scheme 43

 

Scheme 44



Scheme 45

 

Scheme 46


 

The functionalised anthranilic acid 132 reacts as a dinucleophile with the bis(imidoyl)chloride 133 to generate a seven-membered ring and cleavage of the corresponding lactone forms the intermediate. An intramolecular prototropic shift followed by nucleophilic attack of the amidine nitrogen on the ketene yields the quinazolinone skeleton 134. Interestingly, the regioselective cyclisation proceeded to give the more thermodynamically stable six member ring by reaction of the more nucleophillic amidine nitrogen. In an effort to improve the chemical yield, an ester derivative of the anthranilic acid was employed. A complex reaction mixture was, however, obtained in the stoichiometric reaction of the anthranilic ester with the bis(phenylimidoyl)chloride 133.

 

13.    Synthesis of fluorinated quinazolinones

Smith et al. have developed a one-step synthesis of 4(3H)-quinazolinones 137 by employing 2-fluoro-substituted benzoyl chlorides 135 and 2-amino-N-heterocycles 136 in a cyclocondensation, Scheme 4661.

 

The quinazolinone precipitates immediately after treatment of a dichloromethane solution containing the required heterocycle and diisopropylethylamine with the acyl chloride at room temperature. The yields are, however, low to moderate, and in most cases, the major products are the corresponding amides.

The experimental results reveal that, as the number of fluorines on the benzoyl chloride decreases, the isolated yields of the cyclised product also decrease. The introduction of a nitro group at the 5-position enables the ring closure to occur more efficiently, due to the ability of the p-nitro group to promote the nucleophilic aromatic substitution reaction. The most plausible mechanism for quinazolinone formation is initial nucleophilic attack of the ring nitrogen on the benzoyl chloride followed by intramolecular nucleophilic substitution of the 2-fluoro substituent. This proposed mechanism is supported by the fact that the ring nitrogen is the most nucleophilic atom in 2-aminopyrimidine62.

 

14.    Approaches to luotonins and rutaecarpine:

Luotonins A–F  139-144 were isolated from the aerial parts of Peganum nigellastrum, a plant that has traditionally been used in Chinese medicine, Scheme 47.63

 

Scheme 47

 

Due to its potent biological activity, luotonin A 139, (which has an IC50 value of 1.8 mg/ml against murine leukaemia P-388) has been the target of numerous syntheses. A number of naturally occurring 2, 3-disubstituted quinazolinones exist that possess a high biological activity. Among these, vasicinone, luotonins 139-144 and rutaecarpine 145 have received much attention from the synthetic community. Indeed, synthetic approaches to some of these molecules published before 2003 have been reviewed recently by Bergman64.

 

Harayma et al. have reported a simple convergent synthesis of luotonin A 13965. Rings A, B, D and E are present in the starting materials. The route commences with the alkylation of 146 by 147 under basic conditions to give 148, Scheme 48.

 


 

Scheme 48

 

 


Scheme 49

 

Completion of the synthesis is achieved by intramolecular palladium-assisted coupling to generate ring C. This process was optimised by using tricyclohexylphosphine and potassium acetate, furnishing luotonin A in 86% yield. Even in the absence of the phosphine ligand, the reaction proceeded in 61% yield. This synthetic methodology was extended to synthesize rutaecarpine 145 from 149, Scheme 49.

 

Mhaske and Argade have reported a general high-yielding route to luotonins A, B and F with the key step being a regioselective lithiation, which allows the construction of the C ring in these compounds66. LDA, s-BuLi, t-BuLi and n-BuLi were tested in the presence and absence of TMEDA over a temperature range from 0 to -78°C. This is a high-yielding route and could be potentially useful for the generation of analogues, as well as a range of other natural and synthetic polycyclic compounds.

 

Lee et al. reported the condensation of 150 based on the observation that N-arylbenzimino chlorides condense with anthranilic acid.67 In this case, pretreatment with gaseous or concentrated hydrochloric acid improves the yield of the reaction. In terms of strategy, this route follows Ganesan’s synthesis of luotonin A 139, with 150 being the key intermediate used to construct rings D and E, Scheme 5068.

 

Scheme 50

 

Using this simple procedure, it was also possible to synthesise, among other molecules, the antibiotic, trypanthrine 153, via ozonolysis of the olefin 152, which was prepared from substrate 151, Scheme 51. A similar process was employed for the synthesis of rutaecarpine 145.

 

The Povarov reaction is an important method for the construction of tetrahydroquinolines in a multicomponent fashion, Scheme 5269. It may be viewed as either a concerted Hetero-Diels–Alder reaction or a stepwise Mannich process. This reaction may be carried out in either protic or Lewis acidic conditions. Oxidation of the tetrahydroquinoline ring furnishes a quinoline. Both intra and inter-molecular Povarov cyclisations have been used to synthesize luotonin A 139.

 

Twin and Batey have disclosed a convenient route to luotonin A by use of an intramolecular Povarov reaction. Scheme 5370. In a method developed by Mazurkiewicz, propargylamine was added to isatoic anhydride to afford intermediate, which is subsequently converted into its amide derivative71. Amide intermediate undergoes cyclisation–dehydration in the presence of Hunig’s base, triphenylphosphine and iodine and then rearranges on treatment with piperidine and silica gel to produce the advanced intermediate, which upon hydrolysis, followed by Dess-Martin periodinane mediated oxidation to aldehyde, which allows for the formation of imine 154 which then undergoes Povarov cyclisation in an inverse-electrondemand Hetero-Diels–Alder reaction and is subsequently oxidised to yield luotonin A 139.


 

Scheme 51

 

Scheme 52


 

 


Scheme 53

 


Osborne and Stevenson  reported an intermolecular Povarov cyclisation to achieve the formal total synthesis of luotonin A72.  N-Acetyl-2-azetine 155, a compound readily available in gram quantities from cheap starting materials, was reacted with 156 in the presence of a Lewis acid catalyst to afford quinoline 157 in 78% yield following the addition of HCl to an acetonitrile solution, Scheme 54. Subsequent treatment of 157 with sodium ethoxide in ethanol gave rise to the lactam 150, which, as mentioned previously, can be converted into luotonin A 139 using 2-sulfinylaminobenzoyl chloride.68

Scheme 54

Chavan and Sivappa published an efficient route to the related alkaloid rutaecarpine 145, Scheme 5573. Generation of the indole is achieved by use of the Fischer indole synthesis, as previously disclosed by Kokosi et al74. The synthesis of N-aryl hydrazone 159, an important intermediate in the synthesis of rutaecarpine, was obtained by employing a Dieckmann cyclisation of ester 158. This route allowed easier access to rutaecarpine 145.

 

Scheme 55

 

Scheme 56

15.    Quinazolinone formation using 1-acetyl-1-methylhydrazine:

Peet et al. demonstrated that 2, 3-disubstituted-4(3H)-quinazolinones such as 165 could be prepared from the cyclisation of 2-amino-benzoic acid N-acetyl-N-methylhydrazide 163 under acidic conditions75. The latter compound was obtained from the reaction of o-nitrobenzoyl chloride 160 with 1-acetyl-1-methylhydrazine 161 to give the corresponding substitution product 162 in 64% yield, followed by catalytic reduction of the nitro group using 10% Pd/C. This aniline intermediate 163 was also prepared by the use of isatoic anhydride 164 (X =H) and 1-acetyl-1-methylhydrazine 161, even though in lower yield, Scheme 56.

 

A suggested mechanism for the cyclisation of the diacylhydrazine 163 involves the initial transfer of the acetyl moiety to the aromatic amino functionality and the resulting 2-[o-(acetylamino)benzoyl]-1-methyl hydrazine then rearranges and dehydrates to form 2-methyl- 3-(methylamino)-4(3H)-quinazolinone 165. The cyclisation furnished the desired product in a respectable 78% yield and this procedure represents a simple and efficient synthesis of 2,3-disubstituted quinazolinones.

 

16.    Fused Quinazolinones

Juan C. J. et al, reported fused dihydroquinazolines of formula 167 were prepared from the corresponding anthranillic acids 166 by heating directly with the desired iminium ether or by reaction of 166 with SOC12, followed by reaction with the desired lactam, scheme 5776.

Scheme 57

 

Further Juan C. J. et al used several reagents for the reduction of 167, including borane, alane, NaBH4, LiA1H4, and others. In general, reduction with a large excess of zinc dust in AcOH/HC1 proved to be the best method. Careful monitoring of reaction progression was required to prevent chlorine removal in the chlorinated analogues (about 15-30 min at 50-60°C). Similarly Fused dihydroquinazolines of formula 169 were prepared from the corresponding anthranillic acids 168, Scheme 58.

 

 

Scheme 58

Jolanta Girniene et al reported the cyclocondensation process to quinazolinone via a benzylthiooxazoline intermediate 171  in the D-arabino series and various series of sugars as D- and L-arabinose, D-xylose, D-ribose (aldopentose series) as well as D-fructose and L-sorbose (hexoketose series).77 Application of the process of anthranillic acid condensation with per-benzylated 1,3-oxazolidine-2-thione led to new homochiral quinazolinone derivatives. Extension of the cyclocondensation process to sugar-derived 1,3-oxazolidine-2-thione (OZT) 170 constitutes a promising extension of this reaction to new basemodified nucleosides and nucleotides78. Condensation of 2-benzylthio-1,3-oxazoline 171 with anthranillic acid in dry ethanol offers an efficient access to the D-arabino derived quinazolinone 172 in good yield Scheme 59.

Scheme 59

 

Scheme 60. Reagents and conditions: (a) Me2CO, reflux for 6 h, (b) CH3COONa, CH3I, 4 h, stirring, (c) NH2NH2H2O, reflux for 6 h, (d) DCC, CH2Cl2, 4 h, (e) MeOH, reflux for 6 h, (f) Br2/CCl4, 30 min, stirring, (g) MeOH, reflux for 3 h, (h) conc. H2SO4, 5-100C, 2 h.


S. K. Pandey et al reported three series of novel and new fused heterocyclic systems, viz. triazolo[4,3-a]-quinazolin-7-ones 174, [1,2,4,5]-tetrazino[4,3-a]-quinazolin-8-ones 175 and indolo[2,3-c][1,2,4]-triazino[4,3-a]-quinazolin-8-ones 176 from the key intermediate 3-(substituted-phenyl)-2-hydrazino-quinazolin-4-ones 17379 scheme 60.

 

ACKNOWLEDGMENT:

The authors are thankful to Dr S. J. Surana, Principal, R. C. Patel IPER for providing the facilities. Authors are also thankful to Late. Prof. Dr. R. A. Fursule for his continuous support.

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Received on 24.02.2010       Modified on 24.03.2010

Accepted on 07.04.2010      © RJPT All right reserved

Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 979-1003