Recent advances in the chemistry of 2-chloroquinoline-3-carbaldehyde and related analogs

This review highlights the recently cited research data in the literature on the chemistry of 2-chloroquinoline-3-carbaldehyde and related analogs and their applications over the period from 2013 to 2017. It covers: synthesis of quinoline ring systems and reactions adopted to construct fused or binary quinoline-cord heterocyclic systems. The biological evaluation and the synthetic applications of the target compounds were illustrated.


Introduction and scope
Quinolines are aromatic compounds that consist of a benzene ring fused with a pyridine heterocyclic system. Quinolines are known also as benzo [b]pyridine and 1-azanaphthalene with one nitrogen atom in one benzene ring and none in the other ring or at the ring junction. Heterocycles containing a nitrogen atom possess high and interesting medicinal and pharmaceutical properties. [1][2][3][4] Montelukast (1) is a drug used as an antiasthma agent (Fig. 1). 5 In addition, quinolines are the main core of many types of natural products, 6,7 drugs, [8][9][10] and were found in many synthetic heterocyclic compounds in order to enhance the biological and medicinal properties. Compounds incorporating quinoline ring system exhibited various biological, 11,12 and pharmaceutical activities e.g. anti-tuberculosis, 13 antiplasmodial, 14 antibacterial, 15,16 antihistamine, 17 antifungal, 18 antimalarial, 19,20 anti-HIV, 21 anticancer, 22 anti-inammatory, 23,24 anti-hypertensive, 25 and antioxidant activities. 26 In addition, the use of quinolines as tyrokinase PDGF-RTK inhibitor, 27 inositol 5 0 -phosphatase (SH 2 ), 28 DNA gyrase B inhibitors as Mycobacterium tuberculosis, 29 and DNA topoisomerase inhibitors, 30 were reported. Nadi-oxacin (2) is a racemic uoroquinolone launched as a topical antibiotic in Japan in 1993 to treat acne and methicillinresistant staphylococcal infections. The S-enantiomer was found to be more active than the racemic mixture and had pharmacokinetic properties amenable to systemic use.    In continuation of the previous researches on the synthesis and reactions of quinolines, 43-47 we described herein the literature survey of different strategies developed so far for the synthesis of 2-chloroquinoline-3-carbaldehyde and their analogs as well as to highlight their reactivity and their use as building blocks in the synthesis of variable heterocyclic systems of potent biological properties.
Aneesa et al., 57 have reported the effect of transition metal ions such as Cu(II), Ni(II), Co(II), and Cd(II) on the synthesis of quinolines through the Vilsmeier reagent with acetanilides 15. Vilsmeier reagent was prepared by reaction of thionyl chloride (SOCl 2 ) or phosphorus oxychloride (POCl 3 ) with N,N-dimethylformamide (DMF). The reactions of each of acetanilide, 2methyl-4-nitro-acetanilide, 2,4-dimethyl-acetanilide or 4-nitroacetanilide with the prepared Vilsmeier reagent afforded the respective quinolines 16 through the mechanistic pathway reported in Scheme 2. Kinetically, the followed reaction is a second order in which it depends on the Vilsmeier reagent and anilide substrate and the rate determining step is the reaction between them.
Scheme 6 Reaction with secondary amine followed by condensation and reduction.
Heating of 2-chloro-3-formylquinolines 16 in methanol containing potassium carbonate and iodine gave the respective esters 63a-q, respectively. The role of iodine is to oxidize the aldehydic group to the corresponding acid followed by condensation with methanol to form the esters 63a-q (70-98%). Reuxing of 63a-q in sodium alkoxides or aryloxides followed by hydrolysis of the ester group in acid medium afforded carboxylic acids 64a-t.  78e-h (Scheme 16). The reactions were carried out using different catalysts such as piperidine, pyridine, triethylamine, sodium hydroxide and L-proline. The best products yield (80-85%) and lowest reactions time were achieved in case of using L-proline as a catalyst. 72 Similarly, multicomponent one-pot reactions of 1Htetrazolyl-amino-quinolines 74a,b with each of malononitrile (75a) or methyl 2-cyanoacetate (75b) and 4-hydroxy-2H-  72 The reaction mechanism for the formation of 1H-(triazolyl)/ (tetrazolyl) amino-quinolinyl-pyrano[3,2-c](chromenones) and (pyranones) 78a-h and 79a-h is reported through initial condensation of L-proline with N-heteryl-quinolines 73a,b or 74a,b followed by nucleophilic addition of the active methylenes, Knoevenagel condensation and intramolecular cyclization with the loss of the L-proline catalyst molecule (Scheme 18). 72 The reaction of quinoline 16a with N-methylpiperazine (80) in the presence of basic medium of potassium carbonate afforded 2-(4-methyl piperazin-1-yl)quinoline-3-carbaldehyde (81) through elimination of HCl molecule (Scheme 19). Heating of quinoline 16a with formamide and formic acid in ethanol for 8 h afforded the fused cyclic 1,2-dihydro-3H-pyrrolo [3,4-b]quinolin-3-one (82). The mechanism of the reaction was illustrated through the initial addition of an amino group of formamide to the aldehydic carbonyl of quinoline 16a, followed by condensation to form N-(

Synthesis of quinolinyl-furan derivatives
One-pot multicomponent reactions of 16 with dialkyl but-2ynedioates 126a,b, and isocyano alkanes 97a-c in acetonitrile gave quinolinyl-furan-3,4-dicarboxylates 127a-q in good yields (Scheme 42). The reaction was proceeded by the nucleophilic attack of carbonium ion of isocyanides to C^C followed by nucleophilic attack of the formed anion to formyl group of 16 to afford the target compounds 127a-q. 87

Synthesis of quinolinyl-pyranopyrazole
A multicomponent reaction of 2-chloro-3-formyl-quinoline (16a) with ethyl 3-oxobutanoate and malononitrile (75a) in water containing sulfonyl methane-diamine as a catalyst gave the respective quinolinyl-pyranopyrazole 161 (Scheme 55). The reaction was initiated by abstraction of active hydrogen from methylene group of malononitrile in the presence of a catalytic sulfonyl methanediamine followed by nucleophilic attack of the formed anion to formyl group of quinoline. Knoevenagel condensation of the produced alcohol produced the corresponding arylidene. Next, hydrazine hydrate reacted with ethyl acetoacetate to form pyrazole derivative which reacted with the formed arylidene in the previous step through Michael-type addition followed by intramolecular nucleophilic cyclization to give quinolinyl-pyranopyrazole 161. 95
Knoevenagel condensation of methoxy derivative 173 with cyanoacetic acid gave the corresponding arylidene derivative 174. Heating of 174 with N-acylbenzotriazole hydroxylamine hydrochloride in a mixture of methanol/water (9 : 1) containing sodium bicarbonate gave N 0 -hydroxy-3-(2-methoxyquinolin-3-yl) acryl imidamide (175). Treatment of 175 with N-acylbenzotriazole in ethanol catalyzed by triethylamine afforded the desired ester derivatives 178a-s. Intramolecular cyclization of 178a-s in boiling ethanol/n-butanol afforded quinolinyl-1,2,4oxadiazoles 179a-s, respectively (Scheme 61). 102 7. Concluding remarks 2-Chloroquinoline-3-carbaldehydes represent an extremely interesting class of organic compounds that can be exploited as precursors and building blocks for the synthesis of a wide range of heterocyclic systems and potent antibiotics for microbial and cancer treatment. In addition, quinoline moiety is the basic skeleton of many naturally occurring alkaloids and anticancer drugs. The recent publications describe the synthetic routes of 2-chloroquinoline-3-carbaldehydes following the Meth-Cohn synthesis using Vilsmeier reagent (DMF + POCl 3 or PCl 5 ) upon heating.
2-Oxo-1,2-dihydroquinoline-3-carbaldehydes are considered as reactive synthons in organic synthesis and obtained from the respective 2-chloro derivative by heating in acetic acid containing sodium acetate. 3-Formylquinolines are reactive towards condensation reactions with amines and hydrazines to produce Schiff bases. Nevertheless, in the last ve years, the synthesis of fused quinoline heterocyclic systems was reported through a condensation reaction of formyl quinolines either with intramolecular cyclization or reaction with sodium azide or from multicomponent reaction with azidotrimethylsilane, isocyanides, and arylamines. Eventually, reactions with active methylene-containing compounds tend to yield the respective fused systems. The synthesis of binary heterocyclic systems has been attracted the researcher's interest in the last years due to the valuable biological and medicinal importance through the incorporation of other heterocycles into quinoline ring system. The present survey highlighted the recently cited research data in the literature on the chemistry of 2-chloroquinoline-3-carbaldehyde besides related analogs and their applications. It is certain that 2-chloroquinoline-3carbaldehydes will continue to attract the attention of many researchers and that improvements in their synthesis, as well as novel transformations of these compounds, will be reported in the literature in the near future.

Conflicts of interest
The author(s) conrm that this article content has no conict of interest.