2-Chloroquinoline-3-carbaldehydes: synthesis and reactions (2012-2017)

This review discuss in details the synthesis and reactions of 2-chloroquinoline-3-carbaldehydes during years of 2012-2017. The reactions are subdivided into groups, according to type of reaction, including reactions of both chloro and/or aldehyde substituents. Most applied reactions have been successfully utilized for synthesis of different biologically and pharmacologically active derivatives


Introduction
In the recent years, the chemistry of 2-chloroquinoline-3-carbaldehydes has received considerable attention owing to their synthetic and reactions versatility, in addition to a wide variety of biological activity. 1 These aldehydes were also used as synthetic intermediates for the preparation of large numbers of heterocyclic systems 2 and stereoselective ligands 3,4 of various importance.
Polyfunctionalized heterocyclic compounds play important roles in the drug discovery and drug analysis processes; about 68% of available market drugs are containing heterocyclic ring system. 5Hence it is not surprising that research on the synthesis of polyfunctionalized heterocyclic compounds has received significant attention.The quinolone or 1-azanaphthalene ring system represent a wide occurrence in the nature as substituted and fused ring derivatives, Its derivatives have been known to display a wide range of pharmacological activities such as antimalarial 6 , anti-bacterial 7 , anticancer 8 , antifungal 9 , anthelmintic 10 , cardiotonic 11 , anticonvulsant and antihypertensive 12 , anti-inflammatory and analgesic activity. 13In addition, Quinoline has a privileged scaffold in cancer drug discovery. 142-Chloroquinoline-3-carbaldehydes has been reviewed during the period from 1979 to 1999 15 and from 1999 to 2011 16 , Herein, in this review, we cover the versatile synthetic methods and reactions from 2012 until 2017.

Synthetic Methods
Two important general procedures are used for synthesis of 2-chloroquinoline-3-carbaldehyde and its derivatives I.

The classical Vilsmeier-Haack reaction
It is the most convenient and traditional route for the synthesis of 2-chloroquinoline-3-carbaldehydes.This strategy consists of a multicomponent reaction that involves processes of chlorination, formylation and cyclization of acetanilides by the action of the Vilsmeier´s reagent DMF/POCl 3 to afford 2-chloroquinoline-3carbaldehydes I (Scheme 1). 17,18

Scheme 12
The aforementioned procedure was further applied via one-pot reaction of 2-chloroquinoline-3carbaldehydes I, 6-aminouracils 38 and dimedone 37. Interestingly, the 6-Me and 6-OMe substituted quinoline aldehydes gave rise to products 40a-c proceeding through intramolecular nucleophilic attack by nitrogen, while the other aldehydes gave products 39a-d resulting from attack by oxygen.The exact reason for this selectivity is at present unclear (Scheme 13). 35

Scheme 13
An environmentally benign strategy to the synthesis of 2-amino-3-cyano 4-H-chromenes 42a-d, via one-pot reaction involving malononitrile, various α-or β-naphthol and aldehydes I in the presence of morpholine in water was developed.It was found that employing this approach, aromatic aldehydes bearing electron-withdrawing groups gave higher yields of the corresponding products in shorter reaction times.(Scheme 14). 36

Scheme 14
Synthesis of highly substituted cyclopentadienes containing quinoline nucleus 46a-j, was described.The initially prepared Knöevenagel adducts 43a-b of 2-chloroquinoline-3-carbaldehydes and malononitrile or ethyl cyanoacetate underwent reaction with acetylenecarboxylates 44a-b and isocyanide 45a-b in dichloromethane at room temperature within 12 h, affording the products in moderate to good yields.Mild reaction condition and prompt isolation of the products are some advantages of this protocol (Scheme 15). 37RKAT USA, Inc

Scheme 15
When the aldehyde I was reacted with urea or thiourea 47a,b and active methylene compounds 48a-b in ethanol and in the presence of drops of acetic acid as a catalyst in one-pot reaction namely Biginelli reaction 38,39 , the corresponding compounds 49a-b and 54a-b was obtained respectively.The carbohydrazide 50 was afforded by reaction of hydrazine hydrate with the ester derivative 49b.Moreover, condensation of 49a with 2-aminophenol 51 in the presence of acetic acid afforded the tetrahydropyrimidine-5-carboxamide derivative 52; while the carbimidate derivative 53 was afforded, if the same reaction was carried out in ethanol (Scheme 16). 40

Scheme 18 ARKAT USA, Inc
A facile and efficient method for synthesis of novel furylquinolines 62a-r was developed via the condensation of 2-chloroquinoline-3-carbaldehydes I with acetylenecarboxylates 44a-b and isocyanides 56a-b and 61.The mixture was stirred in acetonitrile for 12 h at 40 o C.After completion of the reaction, the mixture was cooled to room temperature to afford 62a-r (Scheme 19). 43

Scheme 23
Recently, an one-pot method has been used for the synthesis of new polycyclic compounds articulated around 3-cyanopyridine derivatives 73a-f and 74a-d from 2-chloroquinolin-3-carbaldehydes I, acetophenone derivatives 72, active methylene compounds 69a-b, and ammonium acetate as a source of ammonia in the presence of catalytic amounts of PPh 3 at room temperature (Scheme 24). 47RKAT USA, Inc Scheme 24

Reduction of the aldehyde group
A simple and high yielding method was developed for the synthesis of new (2-chloroquinolin-3-yl)methyl diethyl phosphate 76a-h from the corresponding alcohol derivatives 75a-h, that obtained from the aldehydes I, by using O,O-diethyl chlorophosphate in the presence of NaOH and methylene chloride at ambient temperature (Scheme 25). 48

Scheme 25
The synthesis of a new series of 2-chloroquinolin-3-yl ester derivatives 77a-i was reported via a twosteps protocol from 2-chloroquinoline-3-carbaldehydes I. Firstly, I was reduced using NaBH 4 in methanol to yield the corresponding alcohol derivatives 75a,b,e, which is then reacted with acid chloride in DMF along with activated K 2 CO 3 at room temperature to afford target compounds (Scheme 26). 49

Scheme 27
The quinolinyl methanol 79, when allowed to react with methane sulfonyl chloride in presence of TEA in DCM at 0 °C, yielded the corresponding tetrazolo[1,5-a]quinolin-4-ylmethyl methanesulfonate ester 80, which on condensation with p-hydroxybenzaldehyde in DMF in presence of K 2 CO 3 , afforded the required precursor aldehyde 81.One-pot cyclocondensation of the 81 with anilines 82a-l and mercaptoacetic acid 83 was carried out in PEG-400 at 110 °C to obtain the thiazolidin-4-ones 84a-l in moderate to good yield (Scheme 28). 52Scheme 28

Oxidation of the aldehyde group
2-Chloroquinoline-3-carboxylic acid was prepared by oxidation of I using silver nitrate in the presence of sodium hydroxide. 53Esterification of the carboxylic acid derivative 85 using absolute ethanol and sulfuric acid afforded the ester derivative 86, in a good yield, followed by subsequent hydrazinolysis in boiling ethanol to afford 2-chloroquinoline-3-carbohydrazide 87.The later compound 87 was subjected to react with carbon disulfide in ethanol in the presence of KOH under reflux followed by acidification using diluted HCl to give 5-( 2

Scheme 31
An efficient, eco-friendly method for rapid Knoevenagel condensation of 2-chloroquinoline-3carbaldehydes I with ethyl cynoacetate 69b under ultrasonic irradiation in solvent-free medium by using Nethyl diisopropyl amine (NEDA) as catalyst within short time period (14-20 min) at room temperature was reported.Compared with traditional method, this method is more convenient and reaction can be carried out in higher yield, shorter reaction time and milder condition, without generation of pollution and safer to analyst (Scheme 32). 56

Scheme 32
In addition, a facile, efficient and green methodology for the Knoevenagel condensation reaction was reported by grinding a mixture of hetero aryl aldehydes I and various active methylene compounds 69a,b and 97a,b with catalytic amount of [bnmim]OH, at room temperature.The product was extracted twice from diethyl ether, leaving behind [bnmim]OH.Organic layer washed by brine solution (2×10 mL) and dried over sodium sulfate and the solvent was evaporated under reduced pressure (Scheme 33). 57

Scheme 34
The reaction of 2-chloroquinoline-3-carbaldehyde derivatives I and dimedone in the presence of KF-Al 2 O 3 to afford new pyranoquinolines 100a-d was reported.In this approach, a mechanism was proposed for the reaction course.Reasonable yields (41-50%), easily available starting materials and less expensive efficient catalyst are the key features of this method (Scheme 35). 58n efficient synthesis of novel functionalized 1,8-naphthyridine 101(1-30) and chromeno [2,3b]quinolines 103(1-10) derivatives via cascade reaction of 2-chloroquinoline-3-carbaldehyde I(1-9) and enaminones 35(1-12) or cyclic 1,3-dicarbonyl compounds 102(1-4) was introduced.The crude products of 101(1-30) were purified by recrystallization from 95% ethanol, while the crude products of 103(1-10) were purified by column chromatography to afford the pure products.All of the newly synthesized compounds were evaluated for their in vitro antiproliferative properties against cancer; several compounds were found to have high activities (Scheme 36). 59 synthetic route of novel highly substituted cyclopentadienes containing quinoline nucleus was described, in which a Knoevenagel adducts 104a-c of 2-chloroquinoline-3-carbaldehydes I and malononitrile or ethyl cyanoacetate were prepared.The reaction mixture was stirred in ethanol for 15 min at room temperature.After completion of the reaction, the solid was separated by filtration (Scheme 37). 37heme 37

Scheme 41
A new series of quinoline derivatives 122a-g were synthesized by refluxing a mixture of 2chloroquinoline-3-carbaldehydes I, 1,1-dimethylhydrazine 121, few drops of glacial acetic acid in EtOH for 4 h.After completion of the reaction, distilled water was added to the reaction mixture, the resulting solid was separated by filtration, and recrystallized from ethanol to afford pure products (Scheme 42). 65

Scheme 42
The synthesis of 2-chloroquinoline-3-carbaldehyde phenyl hydrazone derivatives 124a-k by two methods was described.The first method is in solution, by stirring substituted aldehyde I and substituted phenyl hydrazine 123a-c in MeOH at room temperature over 2-15 h, while the second method is in solid state by grinding reactants to form products in short time (Scheme 43). 66

Scheme 57
An efficient and high yielding protocol is reported for the synthesis of new class of 4-anilinoquinolinoquinazoline hybrids 216a-l, 217a-h.The target compounds were prepared first by the reaction of 2aminobenzamide 2 with 2-chloroquinoline-3-carbaldehydes I.After oxidation and chlorination, the

Scheme 60
The behavior of compounds E,Z-219c toward hydrazine hydrate was also investigated.In which hydrazine hydrate was added to solution of compound Z-219c and/or E-219c in ethanol.The reaction mixture was heated under reflux for about 3h.The solvent was evaporated under reduced pressure and the residue was recrystallized from chloroform/n-hexane to give 3-(2-chloroquinolin-3-yl)propanehydrazonic acid 224 (Scheme 61). 79

Scheme 61
On the other hand, heating under reflux a mixture of E-219a or E-219d with the appropriate secondary amine (morpholine 225a or piperidine 225b) for 7-10 h, followed by evaporation of the volatile materials and triturating the residue with diethyl ether afforded colorless 226a-d (Scheme 62). 79

Scheme 62
Finally, a direct and efficient approach to the synthesis of benzo[g] [1,8]

Conclusions
2-Chloroquinoline-3-carbaldehydes were used extensively, as an interesting versatile intermediate, due to the presence of both chloro and aldehyde groups, for synthesis of many chemical compounds possessing diverse biological activities.This survey is an attempt to collect, summarize and organize the different synthetic methods and reactions of 2-chloroquinoline-3-carbaldehydes from 2012 through 2017.Most of 2chloroquinoline-3-carbaldehydes reactions are multi component reaction (MCR), either in a step-wise manner or in a one pot has been achieved successfully.Hence these protocols provide convenient strategies to annelate different heterocyclic nuclei with widespread bioactive pyrans and pyrimidines thereby extending the categories of heterocyclic systems.The strategies may also provide valuable information for further design and development of more active biological agents through various modifications and derivatizations.