Synthesis and biological activity of five-membered

Synthesis and biological activity of five-membered hetero-2,3-annelated quinolin-4(1H)-ones Rádl S. Zentiva, Research Institute of Pharmacy and Biochemistry, Dolní Měcholupy 130, Prague 10, Czech Republic e-mail: [email protected]

Introduction When preparing this review, I attempted to cover all title compounds. The literature search has been done with the Beilstein Crossfire and Scifinder databases including the literature up to the first half of 2004. The basic three-ring containing moieties identified by this search are listed below. Corresponding benzo analogs, if relevant, are discussed in the same part. O

O

O

O N H

O

furo[2,3-b]quinolin-4(9H)-one

O

O N H

N H



O

O S S

N H

S

thieno[2,3-b]quinolin-4(9H)-one

N H

N H thieno[3,4-b]quinolin-9(4H)-one

thieno[3,2-b]quinolin-9(4H)-one

O

O

O

H N

NH N H

N H

pyrrolo[2,3-b]quinolin-4(9H)-one

N H pyrrolo[3,4-b]quinolin-9(4H)-one

Избранные методы синтеза и модификации гетероциклов, том 6

N H pyrrolo[3,2-b]quinolin-9(4H)-one

235

O

O

O N

S

N S

N H

isothiazolo[5,4-b]quinolin-4(9H)-one

O

O

N H

N H pyrazolo[4,3-b]quinolin-9(4H)-one

N

N

N H

N H

N

N

N H

N

thiazolo[4,5-b]quinolin-9(4H)-one

O

H N

N pyrazolo[3,4-b]quinolin-4(9H)-one

N H

thiazolo[5,4-b]quinolin-9(4H)-one

O

N H

S

N H

N H

[1,2,3]triazolo[4,5-b]quinolin-9(4H)-one

imidazo[4,5-b]quinolin-9(4H)-one

1. Chemistry This section is devoted largely to the synthesis of title compounds, their reactivity will be discussed only for some most important cases. 1.1 Furo[2,3-b]quinolin-4(9H)-ones Furoquinoline alkaloids are perhaps the most characteristic class of compounds isolated from the Rutaceae family; some of them were found to possess many interesting pharmacological activities. Most of them can be drawn as a general formula 1, but very often also the corresponding iso-alkaloids 2 are known. R

R

OMe

R

R 2

R

N

2

O

R

R

R

1

Dictamnine Evolitrine γ-Fagarine Kokusaginine Maculosidine Skimmianine Acronycidine Maculine Kokusagine

N

O

3

3

236

O

1

1

R H H H H H H MeO H H

1

2

2

3

R R R H H H H H H H H MeO MeO MeO H MeO H MeO H MeO MeO H MeO MeO -O-CH2-OH H -O-CH2-O-

Isodictamnine Isoevolitrine Iso-γ-fagarine Isokokusaginine Isomaculosidine Isoskimmianine Isoacronycidine Isomaculine Isokokusagine

Серия научных монографий InterBioScreen

It is far beyond the scope of this review to discuss this class of natural compounds in details. For reviews see [1], for minireviews [2]. Here we will discuss only some chemically interesting features of these compounds. One of the general reactions of the 4-methoxy substituted furo[2,3-b]quinoline alkaloids 1 is their relatively easy demethylation to the corresponding 4-hydroxy derivatives 3a that are better characterized as the corresponding 4-oxo derivatives 3b (Scheme 1). The demethylation is described using various agents, e.g., hydrogen bromide in acetic acid [3, 4] or ethanolic HCl [5–7]. In case of compounds bearing more methoxy groups, sometimes also an additional methoxy group was selectively demethylated. Scheme 1 1

R

OMe 1

R

R

OH

1

R

2

R

N 3

O

2

R

N

O

2

R

3

R

3

R 1

R

O

R

R 3a

N H

O

3b

In the quinoline chemistry, it is well known that 4-methoxyquinolines heated with iodomethane in a sealed tube isomerizes into the corresponding 1-methylquinolin-4(1H)-ones. Similar treatment of 4-methoxy substituted furo[2,3-b]quinoline alkaloids provides the corresponding N-methyl furo[2,3-b]quinolin4(9H)-ones, also termed as iso-alkaloids [3, 5−12]. In several cases, also similar treatment with higher aliphatic iodides was studied. Asahina Y. et al. reported [3], that similar treatment of dictamnine 4 with iodoethane provided the corresponding N-ethyl derivative 6. However, reinvestigation of this reaction revealed that a mixture of the N-methyl and N-ethyl derivatives 5 and 6, respectively, was formed. The same was observed also with other furoquinoline alkaloids, i.e. skimmianine [13]. Higher iodoalkanes usually did not react. Dictamnine treated with benzoyl chloride in benzoic anhydride was reported to provide the corresponding N-benzoyl derivative 7, which was easily transferred into Nordictamnine 8 by alkaline hydrolysis [3]. iso-Alkaloids can also be prepared by usual alkylation of the corresponding 9-nor alkaloids with iodomethane or dimethyl sulfate [3]. The described reactions for dictamnine, probably the most studied alkaloid of this type, are shown in Scheme 2. Acronycidine 9 (bearing the 4,5,7,8-tetramethoxy substituent) was oxidized with potassium permanganate to quinone 10, demethylation of which provided 11. The same compound was also obtained by the 4-methoxy demethylation followed by oxidation of the primarily formed 12 [5] (Scheme 3). Избранные методы синтеза и модификации гетероциклов, том 6

237

Scheme 2 O MeI

O

N 5

OMe

O

O

EtI

N

O

4

+

O

N

N

Et

O

5

6

MeI

O

O − OH

PhCOCl

O

N Ph

N H

O

O 8

7

Scheme 3 O

OMe

KMnO 4

MeO MeO

MeO

OMe

N OMe

N O

O O

10

O

O

MeO MeO

9

O

O

N H

O

11

KMnO 4

MeO OMe

N H

O

12

238


Total synthesis of furoquinoline alkaloids followed by either iodomethaneinduced isomerization or by 4-methoxy demethylation, eventually followed by N-alkylation, is a logical way of preparation of furo[2,3-b]quinolin-4(9H)-ones. There are several routes to 4-methoxy derivatives. Often a suitable 3-substituted quinolin-2(1H)-one derivative was employed. For example, starting from 4-chloro derivative 13, the cyclization with silver oxide or basic alumina gave compound 14 in 97% and 40% yields, respectively. Usual dehydrogenation using e.g. Pd/C led to compound 15 convertible (under the action of sodium methanolate) into the 4-methoxy derivative 16 [14] (Scheme 4). Scheme 4 Cl

Cl Cl

N H

R

O

O

N R

13

14

OMe

Cl

N R

O

N R

15

O

16

R = H, Me

Similar approach is depicted in Scheme 5. The starting methyl ester 17 was reduced with lithium aluminum hydride (LAH) to provide hydroxy derivative 18 treatment of which with polyphosphoric acid (PPA) gave the 2,3-dihydro derivative 19. Alternatively, the hydroxy derivative could be chlorinated and then subjected to cyclization as shown in Scheme 4. The 2,3-dihydro derivative 19 could be dehydrogenated or transformed to 20 upon a bromination/elimination sequence [15]. Scheme 5 OMe

OMe CO2Me R

N H 17

O

OH

LAH

R

N H

O

18


239

OMe

OMe

PPA

R

O

N

R

19

O

N 20

R = H, Me

Alternatively, the hydroxyethyl intermediate 18 could be replaced by the corresponding aldehyde 23. Such aldehydes are available by oxidation of naturally occurring isoprenoids or diols of general formula 21 and 22, respectively. This approach suffers from the fact, that the cyclization led to mixtures of the linear and angular products 24 and 25, respectively [16, 17]. The mechanism is not known but the formation of angular products can be explained, at least in part, by the fact observed for dictamnine that heating with PPA led to rearrangement into the corresponding angular tricycle (Scheme 6). Scheme 6 OMe

1

R

2

R

N R

O

O

1

R OMe

R O

21 1

R

2

R

OMe

OH

N R

N 2

O

PPA

R

2

R

N R

22

O

R

24 PPA

+

H

O

23

1

R 1

O

N 2

R

OH

O

R

25

R = H, Me; R1, R2 = H, MeO

Synthesis of furo[2,3-b]quinolin-4(9H)-ones based on the formation of the central pyridine ring (Scheme 7) has been used to prepare some furoquinoline iso-alkaloids and/or their synthetic analogs. Starting anilines 26 treated with ester 27 provided intermediates 28, which were thermally cyclized in boiling diphenyl ether into 29. N-Substituted derivatives 30 were prepared by alkylation under usual conditions. Sodium borohydride reduction than gave hydroxy derivatives 31 and their dehydration led to the target products 32 [18−21]. A series of 9-substituted benzyl-6(or 7)-chlorodioxo derivatives 30 were also synthesized in this way [22]. 240


Scheme 7 1

R

O

EtO2C

R

+

2

R

NH2

3

EtO

R

1

EtO2C

R

2

O

R

R

26

27

R

O

R

1

2 3

R

K2CO3/DMF

O

N H

R

O

2

R

3

R

29

R

O

R R

N 4 R

O

30

1

NaBH4

O

R

R4X

R

reflux

28

O

1

Ph2O

O

N H

3

R

O

R

OH

R

KHSO4

2

N 3

2

O

R

R

R

R

O

N 3

4

O

1

31

4

R

32

Another method for formation the central ring is the biosynthesis of nor-isodictamnine 8 from anthranilic acid and aldose 33 suggested by Wenkert E. [23] (Scheme 8). Surprisingly, no synthetic work using this pathway via compound 34 has been found in the literature using both Beilstein Crossfire and Scifinder. Scheme 8 OH CO2H NH2

HO

+

O

HO H 33

O

CO2H N H

O

34

N H

O

8

Kametani T. and Nemoto H. [24] reported that N-hydroxypyrrolidone 36 (generated from lactone 35 and hydroxylamine in the presence of sodium ethanolate) underwent cyclization (in PPA) leading to linear products 37. However, more recent reinvestigation [25] identified angular compound 38 as a product of this reaction (Scheme 9). Избранные методы синтеза и модификации гетероциклов, том 6

241

Scheme 9 O

O NH2OH

37

PPA

EtONa

O

O

O

35

36

O

N H

EtO OEt

N OH

O

N H

O

38

Likewise, 9-unsubstituted 4-oxo derivatives 3b could be easily converted into the respective 4-chloro derivatives 39. Their reactivity has been used to prepare 4-alkoxy and 4-phenoxy derivatives 40, as well as 4-amino and 4-anilino derivatives 41 [4] (Scheme 10). Scheme 10 1

R

4

OR

R

2

R 1

R

O

1

R

POCl3

2

R

3

R

N H

O

R

Cl

R

R 2

R

N R

39

40

O

4

3

3b

O

N 3

1

R

HN

R

R

2

R

N

O

3

R4 = Me, (un)subst. Ph

R

41

Treatment of furo[2,3-b]quinolin-4(9H)-one 8 with Ac2O provided the 3,9-diacetylated product 42 [21] (Scheme 11). The hydrogenation of 9-methyl 4-oxo derivatives 2 leading to the corresponding 2,3-dihydro compounds 43 have been explored in [8] (Scheme 12). 242


Scheme 11 O

O

O Ac2 O

N H

O

O

N Ac

8

42

Scheme 12 R

O

R

1

O

1

R

R

H2/Pd

2

R

N

2

O

R

3

R

N

O

3

R

2

43

2.2 Furo[3,4-b]quinolin-9(4H)-ones The titled heterocyclic system has been surprisingly studied only very sparsely. Quinolone 44 was prepared from 2-bromo-3,4-methylenedioxybenzoic acid by using a standard procedure adopted from the synthesis of 1-arylquinolones [26]. The vinyl group was introduced upon the 1,4-addition at C(2) with vinyl cuprate to give intermediate 45 in 62% yield. Treatment of this compound with a solution of KMnO4 in aqueous acetone at r.t. provided a 20% yield of 46 and 75% of starting 2-unsubstituted quinolone 44 (Scheme 13). Using higher temperatures and/or other oxidants provided the mixtures containing no 46 [27, 28]. Scheme 13 O

O CO2Et

O O

O

N

MeO

CO2Et

O

OMe

N

MeO

OMe

OMe

OMe

44

45 (62%)


243

O

O

O

+

O O

44 (75%)

N OH MeO

OMe OMe 46 (20%)

2.3 Furo[3,2-b]quinolin-9(4H)-ones Most publications dealing with this class of compounds are devoted to benzo derivative 47 closely related to the alkaloid quindolinone 48 (see Section 2.9) and its derivatives. O

O

H N

O N H

N H 47

48

I am aware of the only paper [29] dealing with tricyclic derivatives involved in the preparation of 52. It is evidently inspired by the Bamberger method of conversion of anthranils to acridanones using nitrous acid. Starting anthranil 51 was prepared from benzoyl chloride 49 in two steps via benzoyl furane 50 as shown in Scheme 14. Scheme 14 O

O Cl

+

O

NO2

Cl

O

SnCl2

NO2

Cl

49

50 (59%)

O Sn/HCl

O Cl

N 51 (15%)

244

O O

HNO2

Cl

N H 52 (43%)


Görlitzer K. et al. [25] reported on the synthesis of quindoline, quindolinone as well as their oxa and thia analogs. Thermal reaction of anthranilic acid with 3-coumaranone 53 provided the target product 47 in 18% yield (Scheme 15). Scheme 15 CO2H

O

O

O

∆

+

O

NH2

N H

53

47 (18%)

Other approaches starting from derivatives of N-tosylated anthranilic acid can be used to prepare the corresponding N-substituted derivatives. For example, anthranilic chloride 54 treated with 55 in the presence of potassium carbonate yielded intermediates 56 in low yields (16−26%). On the other hand, the yield of subsequent cyclization with PPA leading to 57 ranged between 56 and 75% [30] (Scheme 16). Scheme 16

N Ts 54

Ts

O

O Cl R

Br

+ OH

N

R

O O

K2CO 3 acetone

HO

55

56 (16−26%)

O O

PPA

N R 57 (56−72%) R = H, Me, Et

A higher total yield of 47 was achieved upon heating 58 with PPA [31−33]. Intermediate acid 59 could be detected at lower temperatures (Scheme 17). A different approach using either denitrocyclization reaction or nucleophilic displacement of F was applied by us to synthesize the corresponding tetracyclic compounds, which can be easily in two steps converted into the alkaloid quindoИзбранные методы синтеза и модификации гетероциклов, том 6

245

line or its oxa and thia analogs. Salicylonitrile and phenacyl bromide 60 gave moderate yields of either 61 or 62, depending on reaction conditions. The cyclization of intermediate 62 provided good yields of the target compound 47 [34, 35] (Scheme 18). Scheme 17 O

CO2H O

O

PPA

O

N H

(57%)

N H 47

58

CO2H PPA

O

PPA

N H

59

Scheme 18 O CN

CN

Br

+ OH

O

X

O 60

X

X

61

O

O O

H2N

O

NaH DMF

62 (40−50%)

N H 47 (80−91%)

X = F, NO2

To the best of my knowledge, only the reactivity of tetracyclic benzofuro[3,2-b]quinolin-9(4H)-ones has been studied so far (Scheme 19). Furoquinolone 47 treated with POCl3 provided the corresponding chloro derivative 63. In the next step, the chlorine atom was either replaced by the alkoxy or alkylamino group, to give the respective derivatives 64 and 65, or hydrogenated to oxaquin246


doline 66 [35]. Compound 47 treated with P4S10 provided a good yield of the corresponding thione 67 [30]. Methylation of the anion (generated from 47 by the action of NaOH in ethanol) with iodomethane gave the corresponding N-methyl derivative [36]. This is in contrast to the reported [30] O-ethylation of this compound with iodoethane in NaH/DMF. Scheme 19 O

S O

O

P4S10

N H

N H 47

67

POCl3

Cl

OMe O

O

MeONa

N

N 63

64 Me2NH

H2 Pd/C

N O

O

N

N 66

65

2.4 Thieno[2,3-b]quinolin-4(9H)-ones Treatment of a sodium salt of 68 with methyl chloroacetate in DMF provided good yields of methoxy derivative 69, demethylation of which with HCl afforded acid 70 [37] (Scheme 20). Scheme 20 MeO

O

OMe H

Cl

N H 68

S

1. MeONa/DMF 2. ClCH2CO2Me

Cl

N

S

CO2Me

69 (88%)


247

O HCl

Cl

S

N H

CO2H

70

2-Chlorobenzoylacetonitrile 71 treated with phenyl isothiocyanate in the presence of NaH provided sodium salt 72 which was then alkylated with appropriate activated bromomethyl derivatives to give 73. This intermediate treated with sodium hydride provided compounds 74 in good yields [38] (Scheme 21). Scheme 21

O CN

+

Ph N

NaH

S

Ph SNa

Cl

Cl

CN

72

71

O

O Br

HN

O

O CN

R

N Ph

NH2

O

NaH

R

S

DMF

S

N Ph

O

R

74 (60−65%)

73 (51−73%) R = Me, Ph, OMe

Acid-mediated cyclization of 76 using PPA gave good yields of 77. Intermediate 76 was obtained upon treatment of 75 with aniline [39] (Scheme 22). Scheme 22

Ph

CO2Et S 75

248

NH2

aniline

Ph

O

CO2Et H N S

PPA

Ph

76

Ph

N H

S

77 (85%)


Thienoanthranil 79 (generated upon heating of 78 in bromobenzene) gave thienoquinolone 80 [40]. Similarly, thienoanthranil 82 generated from 81 was rearranged in the presence of Fe into 83. On the other hand, the same reaction performed in 1,2,4-trichlorobenzene provided 47% yield of a compound having structure 84 or 85. The same product was also obtained in low yields when compound 83 was heated in 1,2,4-trichlorobenzene [40, 41] (Scheme 23). Scheme 23

S

O PhBr

N3

S

O

O

∆

N

78

N H

79

80 (53%)

S PhBr

O

∆

N

S

O PhBr, Fe

∆

N

82 (89%)

S

83 (68%) C6H3Cl3 (18%)

∆

O

O

O

C6H3Cl3

N3

S

∆ (47%)

or N

S

N

Cl

Cl

81

S

Cl

Cl

84

85

4-Hydroxyquinolin-2(1H)one derivatives 86 were alkylated with propargyl bromide to afford 87. Subsequent thionation led to thiones 88, which were then subjected to the Claisen rearrangement in refluxing chlorobenzene to give 89 (Scheme 24). The formation of these products may be tentatively explained by an initial [1,3] or [3,3]-sigmatropic shift; the exact mechanism remains unclear [42]. Избранные методы синтеза и модификации гетероциклов, том 6

249

Scheme 24 1

R 1

R

OH

O

Br

N R

K2CO3

O

N

O

R

86

87 1

R O

O

P2S5

1

R

PhCl

N

∆

S

N R

R 88

S

89 R = Me, Et, Ph;

R1

= H, Me

2.5 Thieno[3,4-b]quinolin-9(4H)-ones Ester 90 treated with aniline in the presence of acetic acid gave derivative 91, which was then subjected to cyclization into 92 (Scheme 25). Sodium salt of 92 was then methylated with iodomethane to give good yields of 93. It is of interest that similar alkylation with ethyl 4-bromobutyrate gave a mixture of the corresponding N-alkylation and O-alkylation products and that similar acylation with tosyl chloride or ethyl chloroformate gave exclusively O-acylated products. Dehydrogenation of 93 to 94 using several agents (chloranil, SeO2) was described in [43]; in this transformation, sulfuryl chloride was found to be especially efficient [44] (Scheme 25). Scheme 25 EtO2C S O 90

250

O

CO2Et aniline AcOH

S

PPA

S

N H

N H

91

92


O

O MeONa

S

MeI

SO2Cl2

S

N

N

93

94 (70%)

2.6 Thieno[3,2-b]quinolin-9(4H)-ones Methyl thiosalicylate was alkylated with 2-aminophenacyl bromide 95 to give good yields of 96, which could be further condensed into 97. This intermediate was cyclized using PPA. N-Substituted products 98 are formed if the starting compound 95 is N-alkylated [25, 45] (Scheme 26). Scheme 26 R

O CO2Me

Br

+ N H

SH

S

MeONa

R

MeO2C

95

R

NH O

96

NH O

O S

S

PPA

HO

N R

97

98 R = H, Me, Et

A different approach, which can also be applied for the synthesis of N-substituted compounds, is depicted in Scheme 27. Starting anthranilic acid is first transformed into intermediate acid 99 which is then subjected to cyclization using PPA [46]. Similar to oxa analogs (Section 2.3), benzothieno[3,2-b]quinolin-9(4H)-one 101 was prepared via the corresponding intermediates 100 [35] (Scheme 28). Избранные методы синтеза и модификации гетероциклов, том 6

251

Scheme 27 CO2H

O

Cl

+

NH R

CO2H O

NaOH

S

S

N R 99

O S

PPA

N R 98 (51−67%) R = H, Me, Et

Scheme 28 O

X

O

Br

CN

S

+ X

SH

H2N

60

100 (41−66%)

O S

NaH DMF

N H 101 (84−88%) X = F, NO2

Just as in case of the furoquinoline system, N-unsubstituted oxo derivatives could be easily transformed into the corresponding chloro derivatives 102, after which the reactive chloro substituent could be easily displaced upon nucleophilic substitution [35, 46]. Dioxide 104 was prepared from 101 using hydrogen peroxide in acetic acid [46]. Both 101 and dioxide 103 can be thionated with P4S10 to compounds 105 and 106, respectively [46] (Scheme 29). 252


Scheme 29 O S N H

101

H2O2/AcOH

POCl3

Cl S N 102 Me2NH

P4S10

O O O S

S

N H

N H

S

104

105

P4S10

N

O O S

S S

N

N H 106

103

2.7 1H-Pyrrolo[2,3-b]quinolin-4(9H)-ones The reaction of indolylacetic ester 107 with NCS provided reactive chloroindoline species, treatment of which with aniline gave the corresponding 2-substituted indoles 108. Their thermal cyclization in refluxed diphenyl ether provided reasonable yields of linear tetracyclic compounds 109 [47] (Scheme 30). Scheme 30 CO2Me 1. NCS/Cl3CCO2H

N H

107

2. R

H N 1

R

CO2Me 1 R N N H

108 (58−64%)


R 253

O R

∆

N

N H

1

R

109 (86−93%) R, R1 = H, Me

2.8 2H-Pyrrolo[3,4-b]quinolin-9(4H)-ones Thermal cyclization of 110 or 111 in refluxed diphenyl ether provided the corresponding tricyclic derivatives 112 and 113, respectively, in modest yields [48, 49]. The intermediates were obtained as shown in Scheme 31. Scheme 31 NH2

EtO2C

1

N R

+

HO

EtO2C

2

R

HCO2H

1

N R N H

2

R

110 (55−85%) 2

O

R

∆

1

N R N H 112 (57−99%)

MeO2C

N MeS

NH2

O

MeO2C

R

+

O

N N H

R

111

O ∆

O

R

O

O N

N H

O

113 R = H, MeO, Et2N; R1 = cyclo-C6H11, Ac; R2 = H, Cl, MeO

254


Oxidation of 1,2,3,4-tetrahydro-β-carbolines 114 with various oxidants is well documented [50–60], especially with complex natural compounds. Among them, the Winterfeltd oxidation using O2/t-BuOK is very attractive as a method for preparation of condensed pyrrolo[3,4-b]quinolin-9(4H)-ones 115. Further oxidation with MCPBA could be used to obtain 116 (Scheme 32). Scheme 32 2

2

R

R

O

O2

N

N H

1

114

R

N R

t-BuOK

N H

R

1

R

115

2

R

O

MCPBA

N R N H

1

R

116 MCPBA - m-chloroperbenzoic acid; R = Alk; R1 = H, Alk; R2 = H, Alk, Ar, AlkO; R+R1 = (un)substituted 5- or 6-membered cycle

2.9 1H-Pyrrolo[3,2-b]quinolin-9(4H)-ones Most compounds of this class are tetracyclic quindolinones. Inadequately studied tricyclic compounds are described in [61]. Upon hydrogenation over Raney nickel, 3-nitroquinoline derivative 117 provided tricyclic compound 118, treatment of which with N,N-dimethylaminoethyl chloride gave a 5 : 2 mixture of 119 and 120 (Scheme 33). Scheme 33 OEt

OEt NO2

N 117

H2/Ra−Ni

NMe2

N

H N

Me2NCH2CH2Cl + − Bu4N Cl, NaOH

118


255

N O

O N

H N

+ N

N H N 119

120

Fichter F. and Boehringer R. reported that treatment of bis(2-nitrobenzyl)malonate 121 with NaOH provided the so-called dioxyquindoline, whose treatment with HI/P led to the alkaloid quindoline [62]. Structure of dioxyquindoline was tentatively identified as 122. Later Görlitzer K. [63] repeated the experiment and established the correct structure of dioxyquindoline as 123 (Scheme 34). Scheme 34 OH

O

N O2N

O2N

N H 122

NaOH

EtO2C EtO2C

EtOH

NO2

121

OH N

NO2 N O

123

Görlitzer K. also developed a methodology for the conversion of dioxyquindoline 123 into quindolinone 48. Treatment with ethyl bromoacetate and NaHCO3 gave quindoline-N-oxide 124, which was then rearranged into 125. The reaction of 125 with EtONa in EtOH led to quindolinone 48 (Scheme 35). A different approach is shown in Scheme 36. Methyl anthranilate treated with phenacyl bromide 126 gave a moderate yield of 127. This intermediate was either deprotected to 128 and cyclized upon treatment with sodium methanolate to give quindolinone 48, or was first treated with sodium methanolate in benzene to give 129, acid cyclization of which led to tosylated quindolinone 130. As most of the previously mentioned methods, the yield of quindolinone is low [65] (Scheme 36). 256


Scheme 35 OH N

H N

1. BrCH2CO2Et 2. NaHCO3

N O

N O

123

124 (79%)

OAc Ac2O

O

H N

H N

EtONa EtOH

N

N H

125 (34%)

48 (90%)

Scheme 36 Ts

O CO2Me

+ N H

NH2

Ts

O

H N

MeO2C

126

NH2 O PPA

127 (53%)

O

H N

N H

128 (57%)

Ts

NH O

MeONa

H N

MeONa

MeO2C

127

NH

Br

48 (30%)

H N

O PPA

Ts N

HO

N H

129 (32%)

130 (22%)


257

Much better yields were reported for the method shown in Scheme 37. This method has been used by several groups for the synthesis of quindolinone derivatives 133, which were then transformed into the corresponding quindoline derivatives for biological screening. Treatment of 131 with anilines gave good yields of 132, whose cyclization with PPA led to 133 [32, 65−69]. Scheme 37 1

2

R

HN

CO2H O N H

R

CO2H O

2

R X

+

N

N H

R

131

1

R

R

132

2

PPA

1

R

O

R

N R

N H 133

X = Cl, Br; R = H, Me, Hal; R1 = H, Me; R2 = H, Hal

Treatment N-ethoxycarbonyl anthranilonitrile with 2-fluoro- or 2-nitrophenacyl bromide 60 (NaH or K2CO3 in DMF) provided low yields of 134. The cyclization of 134 (NaH/DMF) with elimination of the ethoxycarbonyl group led to quindolinone 48 [35] (Scheme 38). Quindolinone 48 was [70] methylated on the quinolone nitrogen atom to give 135. On the other hand, methylquindolinone 136 ethylated under similar conditions gave a mixture of N-ethyl and O-ethyl derivatives 137 and 138, respectively in a low yield [64] (Scheme 39). Scheme 38 O

258

CO2Et

O

Br

CN N H

X

CO2Et N

+ X

H2N

60

134 (25−40%)


O NaH DMF

H N

N H 48 (77−90%) X = F, NO2

Scheme 39 O

H N

O 1. NaH/DMF 2. MeI

N H

H N

N

48

135

O N N Et

O N N H

137 (9%)

1. NaH/DMF

+

2. EtI

OEt N

136

N 138 (14%)

Similar to furo[3,2-b]quinolin-9(4H)-ones and thieno[3,2-b]quinolin-9(4H)ones, 1H-pyrrolo[3,2-b]quinolin-9(4H)-ones are easily converted into the corresponding chloro derivatives, which were subjected to nucleophilic substitution (especially with anilines) to give tetracyclic analogs of the antineoplastic drug amsacrine (see Section 3). Scheme 40 shows the above transformation of unsubstituted quindolinone 48 via the corresponding chloro derivative 139 into amsacrine derivatives 140 [66, 69]. Quindolinone 48 and its N-methyl derivative 135 were also easily thionated with P4S10 to give 141 and 142, respectively [64] (Scheme 40). Избранные методы синтеза и модификации гетероциклов, том 6

259

Scheme 40 O

S

H N

N H

H N

P4S10

N H

48

POCl3

141

R

Cl

R

H N

NH

H N

NH2

N

N 139

O

140

S

H N

P4S10

N

N

135

142

H N

2.10 Isothiazolo[5,4-b]quinolin-4(9H)-ones This class of compounds was extensively studied in relation to the isosteric replacement of antibacterial quinolone-3-carboxylic acids (see Section 3). Starting benzoylacetate 143 treated with reactive imidothioformates 144 gave quinolones 145, oxidation of which with MCPBA yielded 146. Regioselective displacement of the sulfinyl group by sodium hydrosulfite in aqueous THF provided the corresponding mercapto derivative and its treatment with hydroxylamine-O-sulfonic acid led to the cyclic product 147 [71, 72] (Scheme 41). Scheme 41 R

O F F

CO2Et

O

N

+

Cl S

F

F F

CO2Et N

S

R 143

260

144

145


O F

MCPBA

O CO2Et

F

N

S

O

O

F

1. NaSH

NH

2. H2NOSO3H

F

S

N

R

R 147

146 R = Me, Et, cyclo-C3H5, 4-FC4H6

The synthesis of some isothiazolo[5,4-b]quinolin-9(4H)-ones 149, 150 from 2-alkylsulfanylquinolones 148 and O-mesitylenesulfinyl hydroxylamine (MSH) was reported [73]. An equivalent amount of MSH in the presence of K2CO3 led to a mixture of 9-alkyl and 9-unsubstituted compounds 149 and 150, respectively, while 2 moles of MSH without base provided only the N-unsubstituted product 150 (Scheme 42). Scheme 42 O

O 1 eq. MSH K2CO3

O

R

N N 1 R

O

S

+

N

R N H

149

S

150

R N H 148

S 1 R

O 2 eq. MSH

N

R N H

S

150 R = H, 6-t-Bu, 6-MeO, 6-Cl, 6-Br, 8-Et, 8-Ph, 8-CF3; R1 = Me, Pr, Bn, Ph

2.11 Thiazolo[5,4-b]quinolin-9(4H)-ones Compounds 152 were obtained in moderate yields (53–57%) by fusing 3-arylrhodanines 151 with anthranilic acid and sodium acetate. Similarly, compounds 154 have been prepared from thiazolidin-4-one 153 [74, 75] (Scheme 43). Избранные методы синтеза и модификации гетероциклов, том 6

261

Scheme 43 O CO2H R

S

+

NH2

O

S

AcONa

S

R

S

N Ar

N Ar

N H

151

152 (43−57%)

O CO2H R

S

+

AcONa

Ar

NH2

O

S Ar

R

N Ar

N H

153

N Ar

154 (80%)

2.12 Thiazolo[4,5-b]quinolin-9(4H)-ones The reaction of activated chlorobenzoic acid 155 with aminothiazole 156 provided a reasonable yield of 157. This intermediate was cyclized by POCl3, while the formed chloro derivative was hydrolyzed (without isolation) to 158. Silver salt of this compound was then alkylated with iodomethane to provide low yields of 159 [76]. Similarly, compound 160 was cyclized (using POCl3–PPA) into 161 [77, 78] (Scheme 44). Scheme 44 O2N

CO2H Cl NO2

+

CO2H

O2N

N H2N

Bn

S NO2 156

155

N H

O2N

Bn NO2

N H

158 (58%)

262

O N

2. H2O

S

157 (62%)

O 1. POCl3

N

Bn

MeI

O2N

N Bn

S

N

S

NO2 159 (28%)


O

EtO2C

R

N SMe S

N H 160

POCl3

R

N SMe

PPA

S

N H 161

R = H, Me, F

Phthalimide derivative 162, easily generated from commercially available 2,4,5-trifluoroacetophenone, treated with cyclopropyl isothiocyanate in the presence of sodium hydride provided the corresponding sodium salt, which was then methylated with iodomethane to give 163. Subsequent cyclization with sodium hydride gave quinolone 164 and its deprotection and oxidation with MCPBA provided 165. Subsequent treatment with sodium hydrosulfite and triphosgene gave good yields of 166 [79] (Scheme 45). Scheme 45

O

F

O

F N

O N

1. c-C3 H5 NCS, NaH

O

F

O

2. MeI

F

HN

F

NaH THF

O SMe

F 163 (78%)

162

O O F F

N

O

N

1. N2H4, EtOH (87%)

F

O SMe

2. MCPBA (74%)

F

NH2 N

164 (53%)

2. triphosgene

O

165

O 1. NaSH/THF

S

F

H N

F

S

O N

166 (61%)


263

2.13 1H-Pyrazolo[3,4-b]quinolin-4(9H)-ones and 2H-pyrazolo[3,4-b]quinolin-4(9H)-ones In a search for new antimalarial drugs, chloroderivative 171 was prepared as a key intermediate. Its synthesis started from anthranilic acid 167 treatment of which with diketene gave benzoxazine 168. The reaction 168 with methylhydrazine gave pyrazole derivative 169. Cyclization of this compound with PPA provided 170 convertible into 171 with POCl3. If the cyclization is done with POCl3, chloro derivative 171 is obtained [80]. On the other hand, its acid hydrolysis gave quantitatively 170 (Scheme 46). Similar to 169, its N-arylpyrazole analogs provided the corresponding 1-arylpyrazolo[3,4-b]quinolonones [81, 82]. Scheme 46 O CO2H R

O

+

O

NH2

O R

O

MeNHNH2

N

167

168

O PPA

N R

N H

N

170

CO2H POCl3

N R

N H

H2O, H

N Cl

169 POCl3

N R

R = H, Cl

+

N

N

171

An interesting rearrangement leading to 172 was discovered by DeWald during the attempted synthesis of 1-desmethyl zolazepam by heating with pyridine hydrochloride [83]. Isomeric 1,3-dimethyl derivative 174 was prepared by heating of 173 with DMSO (Scheme 47). Prolonged reflux of 175 with 1,2,4-trichlorobenzene gave rise to its thermolysis yielding a mixture of 176 (68%) and 177 (4%) [84] (Scheme 48). 264


Scheme 47 O

N

N

Py·HCl

N

O

H N

H N N

N

O

N

N H

N F

F zolazepam

172 (74%)

O N

NH2

N

DMSO

O

N

∆

N H

F

N

174 (70%)

173

Scheme 48 N N Cl O N 175

O

O

Cl 1,2,4-C6H3Cl3 ∆

Cl N N H

N

N

+

176 (68%)

N N H 177 (4%)

An extensive study on the pyrazolo[3,4-b]quinoline system has been done by our group in connection with possible antiviral activity of these compounds [85–94]. Based on the known preparation of 179 by extrusion of elemental sulfur [95] from thiadiazine 178, we developed synthesis of N-unsubstituted derivative 181 via acid 180. Alkylation of 179 gave selectively 2-methyl derivative 182, which was hydrolyzed to 183 and cyclized to the corresponding 2-methyl derivative 184 (Scheme 49). A series of similar analogs were prepared analogously [86]. It should be noted that the N-unsubstituted compound 181 cannot be prepared by similar cyclization of 185. It is well documented [96] that such cyclizations give pyrazolo[5,1-b]quinazolin-9-ones 186. Избранные методы синтеза и модификации гетероциклов, том 6

265

Scheme 49 O

O

CO2Et

OEt 1. CS2, NaOH

S

2. N2H4

N H

NH2

S

Cl

NH

N H

NH2

178

EtO2C

O

HO2C N

N

N H

N H

N H

179

−S

N

N

PPA

N H

N N H

N H

180 (85%)

181 (88%)

1. NaH/DMF 2. MeI

O

HO2C

EtO2C

N

N N

N H

N H

182 (86%)

183 (88%)

N

185

N H

N

184 (87%)

N N

PPA

N

N H

O

O

CO2H N H

N

PPA

H N N

N H

N

186a

186b

Treatment of 1-unsubstituted compound 181 with POCl3 gave 187, which can be selectively alkylated at position 1 to give the corresponding derivatives, e.g. compounds 188 and 189. Hydrolysis of this compound gave the above mentioned 1,3-dimethyl derivative 174 [86]. Similarly, some 4-alkylamino derivatives were hydrolyzed under slightly acidic conditions to give the corresponding oxo derivatives. As an example, Scheme 50 shows the formation of 1-(2,3-dihydroxypropyl) derivative 191 from compound 190 [92]. This methodology avo266


ids the use of hazardous diketene and can also be applied to prepare various 1-substituted derivatives. Scheme 50 Cl

Cl N

N

N H

KOH/DMSO (MeO)2SO2

N N 188

Cl

HN

N

N

189

H2O, OH−

N

187

N

O N N H

N

174 (81%)

R

O

RNH2

N

H2O, OH−

N

N

O

O

O

O 190

N N N H HO 191

HO

We have studied the alkylation of N-unsubstituted compound 181 as well as of N-monomethylated compounds 174, 184, and 172 (Scheme 51). High selectivity was found for alkylation of not only 174 and 184 but also 9-methyl derivative 172. Only trace amounts, if any, of the corresponding O-methylation products were detected by TLC. It is of interest that the site of the N-alkylation could be easily predicted by analyzing the UV spectra of the starting compound. The UV spectra of compounds 174 and 192 differ only by the intensity of the peaks at 340 nm. Similarly, compounds 184, 172, and 193 had peaks at 370 nm. On the other hand, unsubstituted compound 181 showed peaks both at 340 and 370 nm [97]. The demethylation of 1,3,9-trimethyl- and 2,3,9-trimethyl derivatives 192 and 193, respectively, with pyridine hydrochloride gave 3,9-dimethyl derivative 172. This compound can also be prepared upon similar treatment of a mixture of 192 and 193 (obtained by methylation of 181) [86] (Scheme 51). The demethylation strategy applicable to preparation of compound 172 cannot be applied to the synthesis of its methoxy derivatives because of complete O-demethylation under the reaction conditions. Therefore, compound 195 was prepared by PPA-induced cyclization of 194 obtained by similar way [91, 94] (Scheme 52). Избранные методы синтеза и модификации гетероциклов, том 6

267

Scheme 51 O

O N

N H

N H

NaH/DMF MeI

N

N

N N

192

O

N

193

Py·HCl

O N

NaH/DMF

N

MeI

N

174

N

N

(79%)

O

192 (78%)

O

Py·HCl

N

O N

N H

+

N

181

N H

O

N

(78%)

NaH/DMF MeI

184

N NaH/DMF MeI

N N

N

N H

172

193 (77%)

Scheme 52 MeO

S N

EtO2C

MeO N H

N

NH2

N

N H

194

O PPA

MeO N N

N H

195

The above-mentioned findings enabled us to prepare many compounds bearing substituents of interest for the potential biological activities. Some of these are exemplified below [87, 93]. 268


O

2

O 2

RO

RO 1

N N 3 R

N R

N 1 R

N

N 3 R

R1, R2, R3 = H, Me, CH2CO2H, R2N(CH2)n, R = Me, Et, n = 2, 3

Treatment of 196, obtained as a minor product in cyclization of N-(5-chloro-2-hydroxyphenyl)anthranilic acid with acetic anhydride, with hydrazine led to a good yield of 197 [98] (Scheme 53). Scheme 53 O

O

CO2H

+ N

NH OH Cl

O

Cl

N

O Cl

O

196

N2H4

O

N

N N H OH

Cl 197 (75%)

The mixtures of linear 3-aryl-1H-pyrazolo[3,4-b]quinolin-4(9H)-one 199 and angular 1-aryl-1H-pyrazolo[4,3-c]quinoline 200 were obtained by cyclization of hydrazones 198 under various conditions [99]. Variation in reaction conditions was found to strongly affect the relative content of these products: in refluxed pyridine, 199 is formed as a sole product, while over the ion exchange resin Amberlyst-732, the angular product 200 is predominant (Scheme 54). The reaction of 201 with hydrazine was found [100] to yield derivative 202. Likewise, 2-phenylsulfinyl derivative 203 gave the dioxo derivative 204 [101] (Scheme 55). Избранные методы синтеза и модификации гетероциклов, том 6

269

Scheme 54 O

N

NH2

O

Ar

Ar N H

HN N

Ar

+

N

SMe

N H

198

Ar = Ph Py, reflux Resin, EtOH, reflux

N H

N

SMe

199

200

70% 28%

5% 52%

Scheme 55 O

O CN N

N2 H4

N Ph

Ph

202 (87%)

O

O CO2Et

F

N Et

N H

N

SMe

201

F

NH2

S O

N2H4

Ph

F

O NH

N

F

Et

203

N H

204 (70%)

2.14 1H-Pyrazolo[4,3-b]quinolin-9(4H)-ones Adams W.J. and Hey D.H. described the nitrosation of 206 (prepared from nitro derivative 205) leading to the N-nitroso derivative 207, subsequent cyclization of which in boiling benzene led to derivative 208 [102] (Scheme 56). Scheme 56 O

O NO2

N 205

270

1. SnCl2/HCl 2. Ac2O

H N

Ac

N 206


Ac

O

N

NOCl

O

N

O

N

H N

N N

207

208

The bromo or iodo derivatives 209 treated with aromatic amines provided the corresponding compounds 210 and their treatment with POCl3 gave good yields of 9-chloro derivatives 211. Alkaline or acid hydrolysis then yielded the oxo derivatives 212 [103, 104] (Scheme 57). Scheme 57 NH2

(I)Br N N

HO2C

R

HO2C

+

N

POCl3

N N H

R

209

210

Cl R

O + − H or OH

N N

R

N N

N

N H 212

211 R = Cl, Me, MeO, NO2

2.15 3H-Imidazo[4,5-b]quinolin-9(4H)-ones Imidazo[4,5-b]quinolin-9-one 214 was isolated upon pyrolysis of 213 in a low yield, the major isolated product being compound 215 [105] (Scheme 58). Scheme 58 Ph

Et N

CO2H

N

NO2 213

O

Et ∆

N N

+ N H 214 (4%)


Et N N

Ph O N

O

215 (14%)

271

2.16 3H-[1,2,3]-Triazolo[4,5-b]quinolin-9(4H)-ones Treatment of phenyl azides treated with ethyl cyanoacetate in the presence of EtONa in ethanol at r.t. gave N-phenyltriazoles 216; further heating led to rearrangement into 217. Saponification of the ester group and cyclization of the formed acids 218 yielded triazolo[4,5-b]quinolin-9-ones 219 [106] (Scheme 59). Scheme 59 EtO2C H2N

N3 CO2Et

+

N

N N

EtONa EtOH

EtONa EtOH

r.t.

reflux

CN

R

EtO2C

R

N

216 (74−81%)

− OH

R

217 (48−100%)

O N N

N H

N H

N H

R

HO2C

N

R

PPA

N N

N H

N H

N H

218 (96−100%)

219 (71−84%) R = H, Me, Cl

A method for preparation of N-alkylated derivatives was exemplified [106] by similar synthesis of 3-benzyl derivative 222 from triazole 220 and p-anisidine via the corresponding intermediate 221 (Scheme 60). Scheme 60 OMe

EtO2C

+ NH2

H2N

N N N

∆

EtO2C

MeO

Bn

N H

220

221

N N N Bn

O MeO

N N H 222

272

N N Bn


3. Biological activity Several classes covered in this review have been studied as naturally occurring compounds or their analogs. It is the case for furoquinoline iso-alkaloids, or analogs of quindolinone. Quindolinone derivatives were often used as intermediates in the synthesis of quindoline or its analogs. In spite of the fact, that some compound of these groups are present in herbs used in native medicine, the knowledge on the biological activities of these minor components is very limited. Very often the studies on the reviewed tricycles were inspired by biologically active acridine derivatives, often bearing a substituted amino group at position 9. Probably the most studied acridine-containing drugs of this type are antimalarics, e.g., mepacrine or acranil. During the extensive search in the field of antineoplastic compounds, antineoplastic drug amsacrine was discovered. During the structural modification of these acridine moiety-containing drugs, many other tricyclic analogs have been studied. It is the case of pyrazolo[3,4-b]quinoline derivatives, where compound BL-20803 was synthetized as a potential antimalaric drug [80] and later widely studied for its antiviral and interferon-inducing activities [107]. Later other similar compounds were found to be also antivirally active [85−94]. Since amsacrine [108] was also found antivirally active, a series of its pyrazolo[3,4-b]quinoline analogs were also synthesized [85, 88, 90]. In the course of modification of these structures, the corresponding hetero 2,3-annelated quinolin-4(1H)-ones were often prepared as useful intermediates. There are also several acridanone derivatives with interesting biological activities, e.g. CMA, an efficient interferon inducing and antiviral agent [109]. In the course of its modification, compound VUFB-16150 was found at least comparably antivirally active [87]. HO

N Et

HN

Et

Et N

HN OMe

Cl

Et

OMe

N

Cl

acranil

N mepacrine

MeO HN

H N O

O N

S HN

N N

N

amsacrine

BL-20803

N


273

O

O N

N

N

N CO2Na

CO2H

CMA

VUFB-16150

Antibacterial quinolones have been widely studied drugs during the last 20 years and several very useful drugs of this type are on the market [110]. Besides obvious structure modifications, attempts to substitute the 3-carboxy group necessary for their activity by a different substituents led also to the synthesis of some tricyclic compounds. Isothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione 223 [71, 72] and thiazolo[5,4-b]quinoline-2,9(1H,4H)-dione 224 [79] derived from ciprofloxacin could be mentioned as examples. Especially the former compound seemed to be very promising, however, neither the compound nor any of its derivative reached clinical use. O F N

O

O F

OH

NH N

N

HN

O

N

S

HN ciprofloxacin

223

O F

H N

N

S

O N

HN 224

Of course, many other activities have been reported and are documented, especially in patents, for heterocyclic compounds covered by this review. However, I am not aware of any other clinically used drugs of the type or a drug currently under clinical investigation. Conclusions The quinolin-4(1H)-one moiety is present in a wide range of compounds exhibiting interesting properties. Among the most studied classes of these compounds 274


there are, for example, the antibacterial quinolones and acridin-9(10H)-one derivatives, both of these groups having been treated in numerous reviews and monographs. This review is attempted to outline the chemistry and some interesting features of a less studied subclass of compounds containing the quinolin-4(1H)one moiety bearing a 2,3-annelated five-membered heterocycle.

References 1. 2.

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

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275

24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.

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