Synthesis, Reactions, and Applications

Hindawi Publishing Corporation Journal of Chemistry Volume 2013, Article ID 851297, 13 pages http://dx.doi.org/10.1155/2013/851297

Review Article 2-Chloroquinoline-3-carbaldehyde II: Synthesis, Reactions, and Applications Bakr F. Abdel-Wahab1,2 and Rizk E. Khidre3,4 1

Applied Organic Chemistry Department, National Research Centre, Dokki, Giza 12622, Egypt Shaqra University, Dawadami, Saudi Arabia 3 Chemical Industries Division, National Research Centre, Dokki, Giza 12622, Egypt 4 Chemistry Department, Faculty of Science, Jazan University, Saudi Arabia 2

Correspondence should be addressed to Rizk E. Khidre; [email protected] Received 13 May 2013; Accepted 17 September 2013 Academic Editor: Patricia Valentao Copyright © 2013 B. F. Abdel-Wahab and R. E. Khidre. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This review deals with synthesis and reactions of 2-chloroquinoline-3-carbaldehyde during the period from 1979 to 1999. The reactions are subdivided in groups that cover the reactions of chloro- and aldehyde substituent as well as reactions which involve both groups. Some of these reactions have been applied successfully to synthesis of biologically important compounds. The main purpose of this review is to present a survey of the literature on 2-chloroquinoline-3-carbaldehyde chemistry and provide useful and up-to-date data for organic and medicinal chemist since such compound has not been previously reviewed in this period.

1. Introduction Over the past two decades, 2-chloroquinoline-3-carbaldehydes and their derivatives have attracted much attention due to their considerable biological and pharmacological activities as antimicrobial [1–7], anti-inflammatory [8, 9], antimalarial [10], and antivirus activities [11]. Despite this versatile importance and in continuation of our previous review articles [12–16], 2-chloroquinoline-3-carbaldehydes have not been previously reviewed in the period from 1979 to 1999. The present review aims to complete our review article about these compounds [14].

2. Synthetic Methods 2.1. Vilsmeier-Haack Reaction. 2-Chloroquinoline-3-carbaldehydes and 2-chloro-4-methyl-quinoline-3-carbaldehyde 1 were prepared from acetanilide [11, 17–21] and acetoacetanilide [17] via a Vilsmeier-Haack reaction (Scheme 1). It was reported that one-pot synthesis of pyrido[2,3b]quinolin-2-ones 2 in moderate yields (22–59%) was archived by treatment of substituted acetanilide with DMF and

POCl3 , to produce compound 1; to this reaction mixture a secondary amide was added in POC13 solution containing one drop of DMF, and the mixture was heated for a further 2-3 h at 75∘ C (Scheme 2) [22].

3. Chemical Reactions 3.1. Substitution Reactions. 3-Formylquinoline-2(1H)-thione (X = S) and -seleno I (X = Se) 3 have been prepared from reaction of 1 with NaXH (X = S, Se). Compounds 3 reacted with primary amine to produce Schiff ’s bases 4 (Scheme 3) [23]. Treatment of 2-(3-(1,3-dioxolan-2-yl)quinolin-2-yl)-Nsubstituted hydrazinecarbothioamide 7, which is prepared by two steps: first reaction of 1 with ethylene glycol followed by reaction with hydrazine hydrate to afford 3-(1,3-dioxolan2-yl)-2-hydrazinoquinoline 6. The latter compound reacted with substituted isothiocyanates and with 𝛼-halocarbonyl compounds which yielded thiazolidinone 8 and thiazoline derivatives 9. The antimicrobial and inotropic and chronotropic activities of the prepared compounds were studied (Scheme 4) [3].

2

Journal of Chemistry R1 O

R1

(i) POCl3 /DMF, 0∘ C (ii) Δ, 80–90, 5 h

R2 N H

CHO

R2 N

R1 = H, COMe; R2 = H, alkoxy, halogen

Cl

1

Scheme 1

O Me

(i) POCl3 /DMF, 0∘ C (ii) Δ, 80–90, 5 h

R1

N H

CHO

R1

N

Ph; R =

Cl

R2 NHAc POCl3 (75, 2-3 h)

R1

N

N

1

O

R2

2

R1 = H, 3-Me, R2 = Ph; R1 = 8-Me, R2 = 4-MeOC6 H4 , 4-ClC 6 H4 , Et, PhCH2

Scheme 2 CHO

CHO H2 NR

NaXH N

N H 3a, b

Cl

1

NR N H 4a, b

X

X

X = S, Se; R = CH2 Ph, CHMe2 , 4-MeC6 H4

Scheme 3 O O

EtOCOCH2 Br

1

HO

O

OH N NH2 NH2

5 6

Cl

N

O

O RNCS N

N H

8

O H N

NHR S

7, 60–85%

S N

R

O

O N

S

O PhCOCH2 Br N

R = Bz, Ph, 4-MeC6 H4 , 4-ClC6 H4

N

N H

N H

N R

9, 35–75%

Ph

Scheme 4

Cyclization of compound 1 with CS2 in EtOH/NaOH or pyridine gave the triazolo[4,3-a]quinoline-1-thione 10. Treatment of 10 with 60% HCO2 H gave the corresponding aldehyde 11. [1,2,4]Triazolo[4,3-a] quinolines 15a–c were prepared and screened as antimicrobial, inotropic, and chromotropic agents. Thus, reaction of 2-hydrazino-3-(1,3dioxolan-2-yl)quinoline 6 with aromatic aldehyde or benzoyl chloride followed by fusion in presence of air underwent cyclodehydrogenation to give the target compounds. The latter compounds were also prepared directly from reaction of compound 1 with aldehyde by fusion (Scheme 5) [24]. Reaction of compound 1 with acetic acid at reflux temperature leads to formation of quinolone 16 which was condensed with ethyl bromoacetate to give ethyl

6-methylfuro[2,3-b]quinoline-2-carboxylate 17 (Scheme 6) [25]. 2H-Pyrano[2,3-b]quinolin-2-ones 20 were prepared in 46–95% by treating compound 1 with HCl to give quinolones 18, which reacted with malonic acid in ethanol in the presence of pyridine and piperidine followed by cyclization in polyphosphoric acid [26]. In a similar manner the related cyanoacrylic acid and its ethyl ester 21 both gave pyranoquinoline-3-carboxylic acid 22 in 90% yield on treatment with PPA (Scheme 7) [18]. Meth-Cohn and coworkers reported replacement of 2-Cl group of compound 1 by H, iodo, OH, SR (R = alkyl, phenyl), CO2 H, Ph, CHO, and N3 (giving the tetrazole) as described in Scheme 8 [18].

Journal of Chemistry

3 O O N N H

N

R

12

Fusion

RCHO O

O O

N S

O O

CS2 /NaOH

N NH

N

NHNH2

H+

R

N R

14a–c

N

11

H

O

+

15a–c

O

Fusion N

N NH

N N

O O

N

H+

N N

PhCOCl/K2 CO3

CHO

S

N

6

10

CHO

O

RCHO Fusion

NHNHCOPh Ph

13

N N

14a

R = Ph, 2-HOC6 H4 , 4-MeOC6 H4

Scheme 5 CHO

Me

CHO

Me

AcOH N

N H 16

Cl

1

EtO2 C

Br

Me CO2 Et

O

O

N 17

Scheme 6 CO2 H

CHO 1

HCl

CH2 (CO2 H)2

R N H

O

R

PPA

C5 H5 N/pip./EtOH

N H 19

18 CO2 R1

R = 7-Me

R N O O 20, 46–95%

O

R = 6-OMe, 7-OMe, 7-Cl, 8-Me

CN CO2 R1 PPA

R N H 21

O

R2

CO2 H R O

N

O

22 R1 = Et, R2 = CN; R1 = H, R2 = CN

Scheme 7

Compounds 1 reacted with alkylthiol to afford 2(alkylthiol)quinoline-3-carbaldehydes 31. In an alternate method compound 31 was also obtained by the reaction of 2-mercaptoquinoline-3-carbaldehyde with ally1 bromide. Allyl thioethers 31 were converted into oximes by reaction with hydroxylamine hydrochloride in the presence of aqueous sodium bicarbonate. Oximes were then oxidized with aqueous NaOCl to give nitrile oxides,

which cyclize spontaneously to dihydro-3H-[1,2]oxazolo[3󸀠 ,4󸀠 :4,5]thiopyrano[2,3-b] quinolone 34 in 81–86% yield. The oxidation was also carried out employing chloramine-T and mercuric acetate (Scheme 9) [27]. Treatment of compound 1 with sodium iodide in acetonitrile followed by reduction with sodium borohydride to afford 2-iodoquinoline 35. Next, Pd(0)-mediated cross-coupling of the latter compound and 2-tributylstannyl acrylic acid,

4

Journal of Chemistry CHO

CHO

CHO

R

R N

R

N

CO2 H

N

(i) Ethylene glycole (ii) BuLi

OH

H2 O

HCl CHO

NaI, MeCN N

SH

S H Na OH Et

CHO R

N 27, 80%

26, 87–95%

29, 96%

30, 87% CO2

CHO

R

t-BuSH or PhSH

R N

I

24

Cl

SR

N

1

28 R = t-Bu, Ph 89%

NaN3 DMSO

(i) Ethylene glycole (ii) BuLi, DMF

CH O

R

CHO

CHO

R

R

N

N

CHO 23

25, 69%

N N N

Scheme 8 CHO

CHO N

R

N

R

Cl

SH

1 aq. KOH/DMF 0∘ C, 0.5 h

Br SH

CHO

N 31

R

N

R

N

S

OH

S

NH2 OH · HCl NaHCO3 , rt N+

O−

N O

NaOCl Et3 N

N 33

R

32

S

R

N 34

S

R = H, Me, Cl

Scheme 9

prepared in 95% yield by Pd(0)-promoted hydrostannylation of propiolic acid, provided compound 36 in 61% yield. Exposure of 36 to diphenyl phosphorazidate (DPPA) afforded the acyl azide 37 in an unoptimized 31% isolated yield. Cyclocondensation of azide 37 with 1-(1-cyclohexenyl)pyrrolidine yielded camptothecin 39 via the formation of intermediate enamine 38 (Scheme 10) [20].

3.2. Addition Reaction on Aldehyde Group. Benzimidazo[2󸀠 ,1󸀠 :2,3][1,3]thiazino[6,5-b]quinoline 41 was prepared by the reaction of compound 1 with 2-mercaptobenzimidazole 40 (Scheme 11) [28]. In the same fashion, [1,2,4]triazolo[5󸀠 ,1󸀠 :2,3][1,3]thiazino [6,5-b]quinolines 43 were synthesized by the reaction of compound 1 with 1,2,4-triazole-5-thiols 42 (Scheme 12) [29].


5 OTHP

CHO N

N

Pd(PPh3 )4 CuI. DMF

I

P

OTHP

CO2 H

N

36, 61%

∙∙

− + N N N

PhO

OTHP

35, 96%

1

PhO

CO2 H

(i) NaI, HCl, MeCN

(ii) NaBH4, MeOH (iii) DHP, TSOH

Cl

Bu3 Sn

OTHP

N

O N

N

N

O

38

37, 31%

N

H N

Xylene, reflux

CON3

O

39, 30%

Scheme 10

OH CHO +

N

H N N

N 40

Cl

1

N

HS N

S 41

Scheme 11 OH

CHO

HN +

R1

N 1

Cl

N N

HS

N

R2 N

42 R1 = H, 6-, 7-, 8-Me, 6-, 7-, 8-OMe, 7-, 8-Cl; R2 = H, Me, Et

S 43

N R2 N

Scheme 12

Reaction between compound 1 and acetone in the presence of piperidine and acetic acid gave 4-(2-chloroquinoline3-yl)-4-hydroxybutan-2-one 44 accompanied with a small amount of chalcone. Reduction of 𝛽-keto alcohols 44 with sodium borohydride yielded the diastereoisomer 1,3-diols 45a,b in 64–92% yield. The intramolecular cyclization of 1,3-diols was performed in DMF containing HCl to produce (2R,4S) 46a and (2S,4S)-2,4-dimethyl-3,4-dihydro-2Hpyrano[2,3-b]quinoline 46b (Scheme 13) [30]. Mg-Al hydrotalcite catalyzes the reaction between compound 1 and nitromethane very efficiently to afford threo (1S,2R)-1-(2-chloroquinoline-3-yl)-2-nitropropane-1-ol 47a

[6]. On the other hand, it was reported synthesis of 1-(2-chloroquinoline-3-yl)-2-nitroethanol 47b and 2chloro-3-(2-nitrovinyl)quinoline 48 from reaction of 1 with nitromethane (Scheme 14) [7]. The synthesized compounds were tested in vitro for their antimycotic activity against Aspergillus fumigatus, Trichophyton mentagrophytes, Microsporum Gypseum, Epidermophyton floccosum and Candida albicans [7]. Grignard reaction of compound 1 with either MeMgI or PhMgI followed by oxidation using pyridinium chlorochromate gave 3-acetyl-2-chloroquinolines 49 [31]. Methyl thieno[2,3-b]quinoline-2-carboxylates 51 were

6

Journal of Chemistry OH

O

CHO Acetone piperidine, AcOH

R N

Cl

R N

1

Cl

44, 43–70%

NaBH4 /MeOH

OH

OH

OH

OH

R

R N

N

Cl

Cl

45b

45a

DMF/HCl

DMF/HCl

R

R

N

O

N

O

46b, 56–84%

46a, 49–56%

Scheme 13 OH

R2

NO2

NO2

R2

1 Mg-Al hydrotalcite (20% w/w) THF, reflux 6–8 h

R N

Cl

NO2

+

R

47a, b threo (100%) R2 = Me (80%), H

N

Cl

48

R1 = H, 7-Me, 6-OMe, 6-Cl, 7-Cl, 5-Cl, 7-OMe

Scheme 14

prepared in 70–80% yield by reaction of ketone 49 with methyl 2-mercaptoacetate in DMF containing anhydrous K2 CO3 followed by cyclization in methanol containing piperidine. Compounds 49 were condensed with aromatic aldehyde to give the corresponding chalcones 52. The latter compounds were cyclocondensed with hydrazine to produce pyrazoles 53 (Scheme 15) [32]. Reduction of compound 1 followed by treatment with phospours tribromide and salicylaldehyde yielded chromeno[4,3-b]quinoline-4-carbaldehyde 54 which was reduced by Pd-C in methanol to produce 3-(3(hydroxymethyl)quinolin-2-yl)benzaldehyde 55 (Scheme 16) [33]. Reaction of 4-amino-5-aryl-4H-1,2,4-triazole-3-thiols 56 with 1 was carried out without solvent using inorganic solid supports (e.g., silica or alumina) either in microwave irradiation [1, 2] or in DMF containing potassium carbonate [5] to give the triazolothiadiazole 57. The synthesized quinoline

derivatives have been assessed for their anti-inflammatory, antibacterial, and antifungal activities (Scheme 17) [5]. 3.3. Oxidation of Aldehyde Group. Oxidation of compound 1 with alkaline silver nitrate in ethanol gave the corresponding acid 53 in 73–75% yields. 2-Chloroquinoline-3-carboxylic acids 58 reacted with either o-phenylenediamine or 4,5dichloro o-phenylenediamine in xylene to afford quino[2,3b][1,5]benzodiazepine-12-ones 54 in 39–72% yield. In contrast the reaction of those acids 58 with 4,5-dimethyl ophenylenediamine yielded benzimidazoles 60 in 60–70% yield (Scheme 18) [34]. 3.4. Condensation Reactions 3.4.1. Reactions with Active Methylene Compounds. Compound 1 was condensed with either acetylacetone or ethyl


R3

7

R4 (i) RMgI N

R2 R1

O O NH+ Cr O

(ii)

N

R2 R1

Cl

1

K2 CO3 /DMF

Cl

O

R4

R3

SH

R −

Cl

CO2 Me

O

R4

R3

CHO

R R1

R =Me R5 = C6 H5 , 4-OMeC6 H4 N

NH R5

R2

N R1

NH2 NH2 · H2 O R3

N

R2

R

S

N

R2

R5

Cl

53

R4 R3

O

R4

R3

CO2 M e

Pipridine MeOH

R5 CHO

R4

S

N 50

R2

49

CO2 Me

R1

51 R = Me, Ph

Cl

R1

52 R1 = R4 = H; R2 , R3 = H, MeO

Scheme 15

CHO

N

(i) NaBH4 , MeOH

O

(ii) PBr3 , C6 H6 (iii) Salicylaldehyde

Cl

CHO

N

1

OH

Pd-C MeOH

CHO

N

54

55

Scheme 16 N S

R1

N

CHO

N

+ R 2 Cl

N SH

N NH2 56

1

MW or DMF/K2 CO3

R1

N

N R2

N H N

Cl

57 R1 = H, OMe; R2 = Me, CH2 Ph

Scheme 17 R1

CHO

AgNO3 /EtOH

N 1

R1

N

R2

H2 N

R2

O NH

CO2 H

Cl

H2 N

R1

R2 = H, Cl xylene

Cl

N H 59

N

58, 73–75%

R2 R2

Me

H2 N

Me

Me

HN

H2 N

Me

R1

N N 60

R1 = H, Me, OMe

Cl

Scheme 18

cyanoacetate to give compounds 61 and 62, respectively [35]. Methyl thieno[2,3-b]quinoline-2-carboxylates 63 were prepared in 70–80% yield by cyclocondensation of compound 1 with methyl 2-mercaptoacetate in DMF containing anhydrous K2 CO3 (Scheme 19) [32]. Chalcones 65 were synthesized from reaction between compound 1 and aromatic or heterocycle aldehydes 64.

The synthesized chalcones were evaluated for their antiinflammatory activity (Scheme 20) [8]. Cyclization of chalcones 65 with hydrazine, phenylhydrazine, or thiourea to yield pyrazolylquinolines 61 and quinolinylpyrimidine-2-thione 62, respectively, was reported. The anti-inflammatory activity of the prepared compounds was studied (Scheme 21) [9].

8

Journal of Chemistry O

O

R4

COMe

R3

Me

Me

COMe

N

R2 R1

Cl

61 R4

R4 R3

CHO

N

R2

1

CO2 Et

R3

CN

EtO2 C

CN

N

R2

Cl

62

R1

R1

Cl

R1 = R3 = R4 = H; R2 = H, Me, OMe R3

CO2 Me R3

SH

CO2 Me

K2 CO3 /DMF

S

N

R2

63 R1 = H, OMe; R2 , R3 = H, OMe, OEt; R4 = H, O2 N R1

Scheme 19 O R1

O

CHO

+

R2

1

N

Cl

R1

R3

NaOH EtOH

R3

Me

N 65, 56–85%

R2

64

Cl

R1 = R2 = OMe, H; R3 = C6 H5 , 4-MeC6 H4 , 4-OMeC6 H4 , 4-FC6 H4 , 4-F3 CC6 H4 , 2, 4-diOMeC6 H3 , 3-pyridinyl, 2, 2-dimethyl-3-furyl

Scheme 20 R4 N N

R4 NHNH2

R3

R1

R4 = H, Ph R1

R2

N 66

R2

O

Cl

S

R3 N 65

Cl

HN

S R1 H2 N

R3

NH2 R2

N

N 67

Cl

R1 = R2 = H; R3 = Ph, 4-OMeC6 H4 , 4-MeC6 H4 , 4-ClC6 H4 , 4-BrC6 H4

Scheme 21

Treatment of compound 1 with acetic anhydride and sodium acetate afforded the corresponding 2-oxopyrano[2,3b]quinolines 72. Compounds were subjected to ammonia to yield the corresponding naphthyridines 73. The synthesized compounds were tested for their antimalarial, diuretic, clastogenic, and antimicrobial properties (Scheme 22) [10]. Cyclization of chloro(cyanovinyl)quinolines 74, prepared from condensation of 1 with 2-(4-chlorophenyl)acetonitrile,

with secondary amines (e.g., piperidine, morpholine, and 4methyl-1-piperazine), gave substituted benzonaphthyridines 75 in 34–98% yield (Scheme 23) [36]. 3.4.2. Reactions with Hydrazine, Hydroxylamine, Hydrazides, (Thio)Semicarbazide, and (Thio)Urea. Quinolino[3,2-f ]1,2,4-triazolo[3,4-b]1,2,4-thiadiazepines 76 were prepared


9 CHO

Ac2 O/AcONa

R 1

N

NH3

R O

N

Cl

R N

O

72

73

N H

O

Scheme 22

CHO

+ R2

R1

N 1

R2

CN

R1

N 74

Cl

Y

HX

R2 R1

CN

N

Cl

N

X Y

75, 34–98% R1 = H, 6, 7-(MeO)2 ; R2 = 4-ClC6 H4 ; X = N, Y = CH2 ; X = N, Y = O; X = N, Y = NH

Scheme 23 R1

N N

CHO

+

1

N

Cl

R2

N

R1

SH

N

DMF N

NH2 56

R2

N S

76 R1 = H, Me, MeO; R2 = C6 H5 , 4-MeOC6 H4 , 4-ClC6 H4 , 2, 4-Cl2 C6 H3

N

N

Scheme 24

by cyclocondensation of 1 with 4-amino-5-aryl-4H-1,2,4triazole-3-thiols 56 in DMF (Scheme 24) [37]. Reaction of compound 1 with phenyl hydrazine yielded 1phenyl-1H-pyrazolo [3,4-b] quinoline 77 [7, 17, 38], whereas interaction with hydroxylamine hydrochloride afforded isoxazole[5,4-b]quinolines 78. Compounds 1 reacted with o-phenylenediamine and ethylenediamine in a 2 : 1 molar ratio to afford N,N 󸀠 -bis-(2-chloroquinoline-3-yl-methylene)o-phenylenediamines 79a and N,N 󸀠 -bis-(2-chloroquinoline3-yl-methylene)-ethylenediamines 79b, respectively. Pyrimido[4,5-b]quinolin-2-ol 80a and pyrimido[4,5-b]quinoline2-thiol 80b were synthesized from reaction of compound 1 with urea and thiourea, respectively (Scheme 25) [17]. Preparation of pyrazolo[3,4-b]quinolines 83 as antiviral agents was reported by treatment of compound 1 with hydroxylamine in EtOH to give oxime 81. Stirring a solution of 81 and SOCl2 in DMF at 0∘ C yielded nitrile 82 which was refluxed with hydrazine in EtOH to give target compounds, which showed MIC of 1.5 𝜇g/mL against herpes simplex virus type 2 and vasodilator activity with an EC50 of 31 Mm (Scheme 26) [11]. Wright and EP reported convenient synthesis of 3-(1Htetrazol-5-yl)quinolin-2(1H)-one 85 from the reaction of 1 with a mixture of formic acid, hydroxylamine hydrochloride, and sodium formate at reflux temperature to give 3-cyano2(1H)-quinolinone 84 followed by treatment of the latter compound with sodium azide and ammonium chloride [21]. On the other hand 4-(1H-tetrazol-5-yl)tetrazolo[1,5a]quinoline 86 was synthesized by the same author from treating 2-chloroquinoline-3-carbonitrile 82 with sodium azide and ammonium chloride at reflux temperature (Scheme 27) [39].

2-Chloro-3-cyanoquinoline 82, which was prepared from compound 1, [40] reacted with hydroxylamine to give amidoxime 87 which on ring closure in DMF containing potassium carbonate yielded isoxazoloquinoline 88 in 32% yield. Reaction of 82 with thiourea furnished 89 which were subjected to ring closure by reacting with chloroacetonitrile in DMF in the presence of potassium carbonate to yield 90 (Scheme 28) [33]. Benzo[b]quinolino[3,2-f ][1,4]thiazepines 91a [41], and benzo[b]quinolino[3,2-f ][1,4]oxazepines 91b [42] were synthesized from reaction of compound 1 with 2-aminothiophenol and 2-aminophenol, respectively. On the other hand, quinobenzodiazepine 92, dihydroquinobenzodiazepine 93, and benzimidazolyl quinoline 94 were prepared from reaction of compound 1 with o-phenylenediamine via oxidation intermediate benzimidazole quinolone to benzimidazolyl quinoline with simultaneous reduction of quinobenzodiazepine 92 to dihydroquinobenzodiazepine 93 (Scheme 29) [43]. 3-Amino-2H-chromen-2-one 95 reacted with compound 1 to give compound 96. Cyclodehydrochlorination of 96 gave benzopyrano[3.4-d] benzonaphthyridinones 97 in 50–60% yield (Scheme 30) [44]. Quinolinecarbaldehyde hydrazones 99 were prepared either by condensation of compound 1 with substituted hydrazinecarbothioamides or by addition of hydrazones 98 to phenyeleisothiocyanate. Cyclocondensation of 2-((2-chloroquinoline-3-yl)methylene)-N-arylhydrazinecarbothioamide 99 with substituted phenacyl bromide gave thiazoles 100. Compounds 99 and 100 were tested against Gram-positive and Gram-negative bacteria (Scheme 31) [4].

10


R

R Y

R1

R1

N

Cl

79a, b

N

Cl

H2 N

NH2 Y Y = C6 H4 , CH2 CH2 R

R

R1

N O

N 78

R CHO

NH2 OH · HCl

PhNHNH2 CH3 CO2 H

R1

CH3 CO2 H

N Cl 1, R = H, Me X

R1

N N

N 77

H2 N

Ph

NH2

CH3 CO2 H R N

R1

R1 = H, 7-Me, 8-Me

N N 80a, b X = O, S

XH

Scheme 25

MeO

CHO

N

Cl

MeO

MeO NOH

H2 NOH · HCl EtOH

N 81

1

N2 H4 · H2 O EtOH

Cl

CN

SOCl2 DMF

N 82

Cl

NH2

MeO

N N

N H

83

Scheme 26

HN N CHO

N 1

CN

HCO2 H, NH2 OH · HCl HCO2 Na

NaN3 , NH4 Cl

Cl

84

N H

N

N

O 85

N H

O

POCl3 HN N CN N

NaN3 , NH4 Cl

N 82

Scheme 27

Cl

N N 86 N N

N


1

11 NOH

(i) NH2 OH · HCl MeCO2 Na

CN

(ii) SOCl2 , C6 H6 (iii) K2 CO3 , DMF

N

Cl

NH2 OH · HCl MeCO2 Na

NH2

NH2

N 87

82

K2 CO3 , DMF

N

O

CN Thiourea, NaOH MeOH

ClCH2 CN

N H

S

O

N 88

Cl

CN

K2 CO3 , DMF

S

N H 90

89

Scheme 28 R

H2 N

CHO

R

+

N 1

N

HX

Cl

R = H, Me, Cl, OMe; X = S, O

N

R

N N

NH

+

N H

X 91

X = NH R = H, Me, OMe

R

N

K2 CO3 /DMF

N

R +

N H

92

N H N

93

Cl

94

Scheme 29 R2

R2

O

O

R1

+1

N

R1

N

N

NH2

R1

O

O

O

O

R2

N 96

95

Cl

97

R1, R2 = H, H; H, OMe; Br, H; Br, OMe; Br, Br; Cl, H

Scheme 30 O

1

R2 NHCSNHNH2

N

R1 N

NH2 NH2

N R1 N

98

NH2

PhNCS

Cl

H N

99

NHR2

S

Br R3

N

R1 N

S Cl

100

R1 = H, 7-Me, 8-Me; R2 = H, MeC6 H4 , cyclohexyl, allyl, Bu, PhCH2 , ClC6 H4 , Ph; R3 = Ph, 4-MeC6 H4 , 4-BrC6 H4

Cl

Scheme 31

R2 N

N

R3

12

4. Conclusions 2-Chloroquinoline-3-carbaldehydes are easily available and have high chemical reactivity due to the presence of two active moieties chloro- and aldehyde functions. This survey attempts to summarize the synthetic methods and reactions of 2-chloroquinoline-3-carbaldehydes from 1979 to 1999.

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