Unravelling the synthetic and therapeutic aspects of five, six and fused heterocycles using Vilsmeier–Haack reagent

The aim of this review is to encapsulate the synthetic protocols and medicinal aspects of a wide range of heterocyclic compounds using the Vilsmeier–Haack (V. H.) reagent. These derivatives act as excellent precursors having different aryl ring functionalities and could be used for the synthesis of a variety of heterocyclic scaffolds. The V. H. reagent, a versatile reagent in organic chemistry, is used to formylate various heterocyclic compounds of medicinal interest. Due to the different chemical interactions, efficacy, and potency of V. H. reagents, plenty of heterocyclic compounds can be synthesized which serve as a constituent in various novel medications and acts as a bridge between biology and chemistry. These carboxylate moieties can effectively cooperate as precursors for several multi-component reactions (MCR) including Strecker synthesis, Bucherer–Berg reaction and post-MCR cyclization, modified variants with various pharmaceutical applications such as anti-tumor, anti-convulsant, anti-chitosomal and so on.


Introduction
Vilsmeier-Haack (V.H.) reaction 1,2 is named aer Anton Vilsmeier and Albrecht Haack in 1927, which is an efficient, affordable and mild reagent used to transform an electron rich aromatic ring to an aryl aldehyde using dimethylformamide (DMF) and phosphorus oxychloride (POCl 3 ). 3The compounds that include at least one heteroatom viz.nitrogen, oxygen, sulphur etc. as a member of the ring system are known as heterocycles. 4,5The implication of heterocyclic scaffolds is re-ected in the eld of medicinal chemistry as an interesting template for the design, synthesis and development of biologically active molecules or drugs including DNA, RNA, chlorophyll, haemoglobin, vitamins and others. 6,7Numerous examples of drugs and bioactive molecules containing different Mamta Chahal was born in Jind district, Haryana state, India.She obtained her Bachelor's degree in 2017 and master's degree in organic chemistry from Kurukshetra university, Kurukshetra in 2019.She is persuing her PhD degree with Dr Mayank Kinger, Associate professor, at Chaudhary Bansi Lal University, Haryana, India.Her research area is the synthetic utility of novel heterocycles.
Sudeep Dhillon was born and grew up in Dahola, Jind, Haryana, India.Sudeep Dhillon obtained his bachelor's degree in Non-medical from Panjab University, Chandigarh in 2015 and his Master's in Organic Chemistry from Maharishi Markandeshwar University, Mullana, India in 2017.He is pursuing his PhD degree from Chaudhary Bansi Lal University, Bhiwani, India with Dr Mayank Kinger, Associate Professor, Chaudhary Bansi Lal University, Bhiwani, India.His current research interests are the synthesis of new biologically potent heterocycles (anti-cancer, anti-Alzheimer, anti-inammatory, etc.).heterocyclic core in their molecular architecture can be found in the literature and also used as agrochemicals in the form of herbicides, fungicides and insecticides to protect crops. 8Literature review reveals that more than 85% of all physiologically active chemical compounds includes heterocycles, thereby emphasizes their signicant role in the modern drugs design. 9n addition, many drugs have been approved and successfully marketed by the FDA in recent years, such as insecticide pronil, 10 azo dye tartrazine 11 used as food colouring, sildenal 12 used to treat erectile dysfunction, dipyrone 13 a strong analgesic and anti-pyretic, celecoxib 14 used to relieve pain, zometapine 15 used to reduces depression, celebrex 16 and ionazolac 17 used against inammation, rimonabant 18 used to reduce obesity etc. (Fig. 1).
Vilsmeier-Haack (V.H.) reagent is an important structural unit in heterocyclic chemistry and occupy a prominent position in the eld of medicinal chemistry due to its remarkable pharmacological activities such as anti-fungal, 19 anti-angiogenesis, 20 anti-cancer, 21 anti-inammatory, 22 anti-depressant, 23 anti-tubercular, 24 anti-viral, 25 anti-convulsant, 26 anti-pyretic, 27 anti-tumor, 28 anti-HIV, 29,30 anti-TB, 31 anti-proliferative, 32 antianalgesic, 33 anti-fertility 34 and anti-bacterial 35  Ginna Kumari was born and grew up in Charkhi Dadri district, Haryana, India.She obtained her bachelor's degree in 2013 from Maharshi Dayanand University, Rohtak, and her master's degree in chemistry in 2016 from Panjab University, Chandigarh, India.She is currently working with Dr Mayank Kinger, in the Department of Chemistry, Chaudhary Bansilal University, Haryana, India.Her research interest is the synthesis of novel heterocycles.
A pictorial representation of several heterocyclic framework synthesized using V. H. reagent is given in Fig. 2.
Keeping in view of the above, we recapitulated the recent progress in the development of enumerate synthetic routes of heterocyclic derivatives using different substrates with the help of V. H. reagent.This review is divided into three parts viz.synthesis and biological perspective of ve-membered, sixmembered and fused rings heterocycles.First section comprising synthesis of ve-membered heterocyclic compounds which has been sub-divided into three categories i.e., cyclization followed by formylation, formylation, miscellaneous while second section includes synthesis of six-membered heterocyclic compounds has been categorized into formylation of pyridine carbaldehyde and miscellaneous.The last section of this segment contains formylation of numerous fused heterocyclic ring system i.e., quinoline, imidazo-pyrimidine, imidazopyridine etc.

Cyclization and formylation of pyrazole
Pyrazoles, 36 also known as azoles, are ve-membered heterocyclic compounds with two closely spaced nitrogen atoms.The chemical reactivity of the pyrazole molecule can be explained by the inuence of the individual atoms.The N atom in position 2 reacts with electrophiles because it is more basic and has two electrons.The N atom in position 1 is not reactive, but loses its proton in the presence of a base.The combined action of the two N atoms causes a reduction in the charge density on C-3 and C-5, exposing C-4 to electrophilic attack (Fig. 3).
Different tautomeric forms of pyrazole carbaldehyde are outlined in Fig. 4. The pyrazole nucleus has been known to exhibited a wide range of biological activities including insecticidal, fungicidal, anti-bacterial, anti-viral, anti-tumor, antihistaminic and anti-depressant agent have been shown in Fig. 5.
In 2020, Kumari et al. 39 reported the comparative study of conventional and microwave-assisted (MW) method for synthesis of 4-formyl pyrazole.In conventional method, phthaloyl dichloride (OPC)-DMF and substrate were stirred at 60 °C for 2 hours while in non-conventional method, phthaloyl dichloride (OPC)-DMF and substrate were heated in microwave at 60  Advantage of this protocol in owing to its simplied operations, convenient process ow, high yield production and the ability to recycle the by-product.The reaction eliminated the need for separate reactions, streamlining the overall process.Due to which, it reduces the complexity of the synthesis, making it easier to perform and manage in the laboratory or on industrial scale contribute to a more efficient and environmentally conscious chemical synthesis.These aspects are crucial in modern organic synthesis, where researchers aim to develop greener and efficient methodologies for drug discovery, agrochemicals and industrial applications (Scheme 4).
In 2016, Padalkar and co-workers 45 synthesized few 3-aryl-4formyl pyrazoles from substituted hydrazones using V. H. reagent (DMF-POCl 3 ) by stirring the reaction mixture at room temperature for 8 hours, in good to excellent yield.Further, 2-[substituted-1H-pyrazol-4-yl]benzothiazoles, benzimidazoles and benzoxazoles were produced using these formyl pyrazoles and diagnosed for anti-bacterial and anti-fungal efficacy.showed good anti-bacterial activity against E. coli and S. aureus with each having MIC value of 62.5 mg mL −1 .The growth inhibitory activity screened against fungal and bacterial strains remains unaffected while electron-donating and electronwithdrawing substituents attached on benzothiazoles, benzimidazoles and benzoxazoles containing pyrazole moiety.The synthesized compounds exhibited signicantly higher antibacterial activity as compared to fungal strains over analyzed microorganisms.The knowledge accrued from this investigation is expected to furnish valuable insights for the advancement of prospective pharmaceutical agents originating from benzimidazole, benzoxazole and benzothiazole compounds, with the incorporation of the pyrazole moiety, in the pursuit of pioneering anti-infective agents (Scheme 10).
In In 2017, Potopnyk et al. 48reported the synthesis of ethyl-1- ).The reaction mixture was stirred at 0-10 °C for 10 minutes followed by stirring at room temperature for 1 hour consequently heating at 65 °C for 2-3 hours to get the desired carbaldehydes.The resultant carbaldehydes were expected to exhibit several bioactivities.Moreover, different methodology was also employed by utilizing Fischer indole reaction conditions with these hydrazones but the reaction did not proceed (Scheme 13).
In 2016, Swami et al. 50synthesized ethyl-4-formyl-1substituted-phenyl-1H-pyrazole-3-carbaldehydes derivatives in excellent yield when substituted phenyl hydrazones were reacted with V. H. reagent in cold condition and followed by stirring the reaction mixture at room temperature for about 3 hours.These formyl pyrazoles were employed as substrate in the multicomponent reaction for producing chemically and medicinally important pyrazole-coupled imidazo[1,2-a]pyridine.This is a straightforward, effectual, safer and environment friendly approach for the synthesis of pyrazole-coupled imidazo-pyridine (Scheme 15).
In 2018, Bala and co-workers 51 synthesized benzothiazole based 4-formylpyrazoles from the corresponding hydrazones using OPC-V.H. reagent (phthaloyl dichloride and DMF) in dioxane, the reaction mixture was blended at 60 °C for 4 to 5 hours.Broth macro dilution assay was used to analyse anti-microbial activity and DPPH radical scavenging assay was employed for analysis of anti-oxidant activity of the synthesized compounds.Among the synthesized compounds, 1-( 6 activity among all assessed compounds when compared to the standard drug ampicillin.According to the structure-activity relationship, the examined compounds were not found to be more effective against bacterial and fungal strains than conventional anti-microbial drugs (Scheme 16).
H. reagent (DMF-POCl 3 ) with stirring in ice-bath, later at room temperature for 15 minutes followed by heating the reaction mixture at water bath for 17 hours, in good yield.The utilization of cost-effective precursors, coupled with simplied work-up procedures, constitutes a signicant synthetic approach for the synthesis of formyl pyrazoles (Scheme 17).
In 2015, Allah and group 53 developed an efficient protocol for the preparation of 4,6-diphenyl-3a,5-dihydro-4H-indazole-3carbaldehyde and 5 ′ -carbaldehyde from 3,5-diphenylcyclohex-2-en-1-one using V. H. reagent in ice-bath for 10-15 minutes and stirred at room temperature for 1 hour followed by heating the reaction mixture at 70 °C for 5 hours, in moderate to good yield.These compounds served as substrate in the production of benzothiazepines, pentahydroxyhexylidene, indazole and N-thiazines.The resulted products were found to have low activities against Gram-negative bacteria as compared to conventional drug chloramphenicol, but they displayed high anti-bacterial action against Gram-positive bacteria (Scheme 18).
In 2016, Bhat and co-workers 55 4-substituted phenyl)ethylidene)benzohydrazide using V. H. reagent blended in ice-bath followed by heating at 70 °C for 4 to 5 hours, in excellent yield.These carbaldehydes were screened by using agar well diffusion method against two bacterial strains Klebsiella pneumonia and S. aureus.These scaffolds were demonstrated an excellent anti-bacterial activity in contrast to standard drug ampicillin (Scheme 21).
In 2022, Mamatha et al. 57 prepared 1-methyl-3-substitutedphenyl-1H-pyrazole-4-carbaldehyde from corresponding hydrazones using V. H. reagent while stirring in ice-bath for 15 minutes followed by heating at 80 °C for 5 to 6 hours, in excellent yield.Further, these formyl pyrazoles derivatives were utilized to prepare pyrazole-conjugated benzothiazole derivatives.These Schiff bases were analysed for their anti-tubercular and anti-cancer activity by means of MTT assay and molecular docking studies.In vitro, compound 2-{2-[(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-5-yl)methylene] hydrazinyl}methoxybenzo [d]thiazole showed anti-tubercular and anti-cancer activities with IC 50 values against the HELA and KB cell lines were found to be 67.65 mg mL −1 and 70.31 mg mL −1 , respectively.Evaluated products were found to be active and have least toxicity towards normal cell lines even at higher concentration with IC 50 value >192 mg mL −1 (Scheme 22).

Formylation of pyrazole
In 2019, Popov and group 58 synthesized 5-chloro-1H-pyrazole-4-carbaldehyde from 1,3-disubstituted-5-chloro-1H-pyrazoles using V. H. reagent on stirring at 0 °C for 10-15 minutes followed by heating at 120 °C for 2 hours, in good yield.The ease of implementation, convenient accessibility of initial substances and signicance of the resulting pyrazoles render this protocol fascinating to researchers.Conversion of simple molecule to bioactive formyl derivatives were regarded as helpful synthons in organic and medicinal chemistry (Scheme 23).
In 2015, Rajput and co-workers 59  H. reagent with stirring at 0 °C followed by heating at 80 °C for 5 to 6 hours, in good yield.Further, these carbaldehydes were used to prepare some new N-arylpyrazole-4-methylpiperidines having good efficacy against a variety of lepidopteran pests.The present study proposes the possibility of a new mechanism of action, although the specic target site remains unidentied.These compounds do not appear to function as established biochemical pathways of insect control because the exact method of action is still an anonymous (Scheme 25).In 2018, Soud et al. 62 synthesized few thiazolinethione-5carbaldehyde from 4-thiazolinethione using V. H. reagent in ice-bath and further stirring the reaction mixture at room temperature for 1 hour followed by heating at 80 °C for 3 to 18 hours, in good to excellent yield.The resulting products could be served as crucial building blocks in the synthesis of a variety of heterocycles exhibited potent biological activity and have good predictions for usage in optoelectronics (Scheme 27).
In 2018, Fadavi et al. 63 developed a new protocol for the preparation of oxazol-5-ones (oxazolones) and 4-arylmethyleneoxazolones through the cyclization of N-acyl-a-amino acids using V. H. reagent (DMF-POCl 3 ), triethylamine in dry chloroform by stirring at room temperature for 1.5 to 2 hours.The resulting compounds were obtained in good to excellent yield in one pot.Notably, this approach boasts the advantages of operating under mild reaction conditions, delivering good to excellent yield of products and offering simplied procedures (Scheme 28).
In 2015, Barman et al. 64 prepared some diformylated-Narylpyrroles from trans-1,4-diaryl-5-hydroxypyrrolidin-2-ones using V. H. reagent (DMF-POCl 3 ) in chloroform at 0 °C and stirred the reaction mixture at room temperature for 40 minutes followed by reuxing for 3 to 8 hours, in good to excellent yield.The operational ease and economic feasibility of this approach, along with the safety, straightforwardness, low cost certainly lead to the method's widespread adoption for possible outcomes of further investigation (Scheme 29).

Synthesis of pyridine carbaldehyde
Pyridine 67 is a basic heterocyclic organic compound with the chemical formula C 5 H 5 N. Due to the presence of an electronegative nitrogen atom this ring becomes electron decient.Unlike benzene derivatives, it is less reactive towards electrophilic aromatic substitutions (Fig. 6).
Pyridine carbaldehyde exist in tautomeric form as shown in Fig. 7.The strong organometallic bases can readily metalates pyridine, suggesting it is more susceptible to nucleophilic substitutions.In pharmacology, it is widely used as antibacterial, anti-viral, anti-histamine, anti-allergic, antibactericide and as herbicide (Fig. 8).
In the rst step, the reaction of DMF-POCl 3 generates an iminium salt (1).The electron rich pyridine approaches the electron decient carbon of iminium salt (1) generating an intermediate (5).Further, the basic hydrolysis of this intermediate (5) results in the formation of the formylated pyridine derivative (6).The resonance stabilization of the iminium ion augments its reactivity, ensuring efficient formylation 68 (Scheme 32).
In 2022, Tasneem et al. 68 showed a signicant drain in reaction time in micellar media by using V. H. reagent in formylation and acetylation in pyridine.This reaction follows second order kinetics when {[V.   synthesis of desired compounds in good to excellent yield.The majority of previously documented approaches have been characterized by the implementation of rigorous reaction conditions, leading to challenges in the subsequent workup process.In light of this, the utilization of micelles has afforded the opportunity to establish a rapid and dynamic methodology for the facile synthesis of formyl and acetyl derivatives of pyridine, thus presenting potent analogues with signicant potential in terms of pharmacological activities (Scheme 33).

Synthesis of miscellaneous compounds
In 2011, Zhang et al. 70 synthesized few pyrimidin-4-(3H)-ones in excellent yield from amino propenamides using V. H. reagent at 0 °C followed by heating at 75 °C for 2 hours in which formylation, halogenation and intramolecular nucleophilic cyclization reactions occurs.The slow conversion was happened when the reaction performed at 60 °C during optimization and even not enhanced by further addition of POCl 3 .The experimental studies have indicated the ideal conditions for synthesizing pyrimidin-4-(3H)-ones involve using 2.5 equivalents of POCl 3 with 1.5 equivalents of DMF in DCM.This approach attracts attention due to easy implementation, uses commonly accessible substrates, requires only moderate conditions, and may produce a diverse array of potentially valuable compounds (Scheme 35).
In 2019, Tang et al. 72 synthesized some Z/E N-(1-chlorovinyl) formamides from 2-phenoxyethanamides using V. H. reagent in ice-bath for 1 hour followed by stirring at 40 °C for 5 hours, in moderate to excellent yield.The introduced C-a-chloro increased the versatility of enamides due to C-a position and phenoxy substitutions at C-b position of N-vinylformamides and Z/E isomers of N-vinylformamides (NVF).It is anticipated that this methodology can be expanded to facilitate the production of a broader range of functionalized NVFs.Additionally, the potential of this approach is expected to be relevant for synthesis of various substrates (Scheme 37).
In 2017, Zarei et al. 73 synthesized some symmetrical and unsymmetrical diacylhydrazines from carboxylic acid using V. Review RSC Advances H. reagent in dry chloroform or acetonitrile at room temperature for 6 to 13 hours, in good to excellent yield.The V. H. reagent is a practical and efficient reagent utilized for the synthesis of acylhydrazines.The simplicity and effectiveness of this method makes it suitable for implementation in large-scale manufacturing process (Scheme 38).
In 2008, Gupton et al. 74 efficiently synthesized some pyrrole carbaldehyde derivatives from substituted pyrrole ring using microwave accelerated V. H. reagent in ice-bath for 45 minutes followed by heating at 100 °C in microwave reactor for 14 minutes, in good to excellent yield.These formylated pyrroles are an efficient and exible precursor for natural products bearing pyrrole ring viz.permethylstorniamide A and polycitones A and B. These formylation reactions offer an effective, adaptable and regiocontrolled technology for the synthesis of signicant class of natural compounds.These processes should also provide quick access to a diverse spectrum of highly functionalized pyrroles for further physiologically prompted SAR investigations (Scheme 39).
In 2005, Prakash et al. 75 prepared 3-chloro-4-hydroxy-6methyl-2H-pyran-2-one by stirring 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one using V. H. reagent in combination with iodosobenzene at room temperature for 2 hours, in average yield.The hydroxy group at position-4 remains intact while the C-C bond in ketone was cleaved during the reaction.The outcomes of this investigation have engendered a keen interest in the comprehensive elucidation of the prospective utilities arising from the synergistic interaction between IOB (iodine(III)bis(tri-uoroacetate)) and V. H. reagent (Scheme 40).
In 2017, Zarei and co-workers 76 synthesized few symmetrical and unsymmetrical acylhydrazines from carboxylic acid with the help of V. H. reagent by stirring the reaction mixture at room temperature for 7 hours, in excellent yield.The implementation of the V. H. reagent obviates the necessity to handle and synthesize acyl halides, rendering the method remarkably efficient, especially for large-scale applications, as the by-products can be readily separated and removed through simple aqueous work-up procedures (Scheme 41).

Synthesis of quinoline carbaldehyde
Quinoline, 77 also known as 1-azanaphthalene or benzo [b]pyridine, is an aromatic heterocyclic nitrogen-containing compound with the molecular formula C 9 H 7 N.It reacts similar to benzene and pyridine as it is a weak tertiary base and forms salts with acids.It participates in both nucleophilic and electrophilic substitution reactions (Fig. 9).Tautomeric structures of quinoline carbaldehyde are outlined in Fig. 10.
It is a common component of different natural products (e.g., cinchona alkaloids) and pharmacological research has shown that numerous substances with different biological effects also contain the quinolone ring system.The anti-bacterial, antifungal, anti-malarial, anthelmintic, anti-spasmodic, cardiotonic, anti-inammatory and analgesic properties of quinoline are discovered as shown in Fig. 11.In the initial step, the mechanism involves the attack on V. H. reagent (1) through C-3 of the indole of the substrate to form resonance stabilized iminium intermediate (7).The intermediate ( 7) containing methyl group, depicted in its mesomeric enol form (8). The ensuing enol tautomer's C]C bond attack on iminium salt (1), thereby yielding the intermediate (9).This process is akin to the prior mechanism as above.This intermediate acts as a nucleophile (9), executing another attack on the iminium salt (1) to produce intermediate (10).Further, the reaction of intermediate (10) through cyclization and subsequent release of dimethylamine to produce intermediate (11)  takes place.The hydrolysis of the intermediate (11) executed under basic conditions lead to the isolation of nal compound (12) 78 (Scheme 42).
In 2021, Abdi and co-workers 79 synthesized chloroquinoline from substituted phenylacetamide using V. H. reagent (DMF-POCl 3 ) at 0 °C for 30 minutes followed by heating the reaction mixture at 105 °C for 22 hours, in average yield.The ve different new chloroquinoline derivatives were synthesized using chloroquinoline which displayed anti-bacterial and antioxidant activities.Among the synthesized compounds, 7chloro-2-ethoxyquinoline-3-carbaldehyde and 2,7dichloroquinoline-3-carboxamide had excellent anti-bacterial activity against E. coli, with inhibiting regions of 12.00 ± 0.00 mm and 11.00 ± 0.04 mm respectively.The compound, 2,7dichloroquinoline-3-carbonitrile demonstrated strong antibacterial action against S. aureus and P. aeruginosa, with an area of inhibition of 11.00 ± 0.03 mm as compared to amoxicillin (180.00 mm).On the other hand, compound 7-chloro-2methoxyquinoline-3-carbaldehyde was found to be active against S. pyogenes, with an area of inhibition of 11.00 ± 0.02 mm.According to the molecular study, 7-chloro-2ethoxyquinoline-3-carbaldehyde may be deemed as an effective molecule for future investigation as an anti-bacterial and anti-cancer medication (Scheme 43).
In 2017, Vellalacheruvu and co-workers 80 synthesized (E)-8-(benzyloxy)-N-(4-(triuoromethyl)phenyl)quinoline-5carbimidoyl chloride from 8-(benzyloxy)-N-(4-(triuoromethyl) phenyl)quinoline-5-carboxamide using V. H. reagent (DMF-POCl 3 ) at 0 °C, then stirred the reaction mixture at room temperature for 1 hour followed by heating at 60 °C for 3 hours, in excellent yield.The tetrazole derivatives of carbamate and urea were produced using the synthesized compound as a precursor by conventional method.This strategic circumvention involved the utilization of anhydrous toluene as the solvent medium, ensuring an impeccably moisture-free environment for the reaction.Furthermore, the entirety of the reaction is meticulously executed within a controlled argon atmosphere (Scheme 44).In 2018, Wei et al. 81 synthesized triuoromethyl thiolation and biofunctionalization of indoles from sodium triuoromethane sulnate (CF 3 SO 2 Na) using V. H. reagent (DMF-POCl 3 ) at 50 °C for 3 hours, in good yield.The method employed was devoid of metallic components, utilized a single reaction vessel, was cost-effective and employed readily accessible reagents such as phosphorus oxychloride (POCl 3 ) or phosphorus oxobromide (POBr 3 ), which provided an additional functional group for subsequent transformations (Scheme 45).
In 2019, Mphahlele and group 78 synthesized few 8-bromo-6oxo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinoline-1,5-dicarbaldehyde from 7-acetyl-5-bromo-2-phenyl-1H-indole-3-carbaldehyde using V. H. reagent and from 1-(5-bromo-2-phenyl-1H-indole-7-yl)ethan-1-one by using V. H. reagent (4.5 equivalents) at 0 °C for 2 hours followed by heating at 50 °C for 3 hours, in good to excellent yield.The most notable aspect of this approach is the synthesis of C-C and C-N bonds within a reaction vessel, resulting in the formation of poly-carbon-substituted pyrroloquinolines.The approach proposed in this study is an excellent tool for the identication of certain new bioactive compounds due to unique characteristics and the signicance of pyrrolo In 2022, Thakafy and co-workers 84 synthesized 2,7-dichloropyrido[2,3-g]quinoline-3,8-dicarbaldehyde from p-phenylenediamine using V. H. reagent (DMF and POCl 3 ) in ice-bath and stirred at 80 °C for 16 hours, in good yield.This carbaldehyde was used as a precursor for the synthesis of chalcones.Further, the resulting chalcones were condensed with mesalazine to produce coloured azo dye.The resulting compound showed maximum absorption at 450 nm by using spectrophotometer.Beer's law was obeyed over the 0.5-27.5 mg mL −1 concentration range with a molar absorptivity 9494.37 mol cm −1 .The limit of detection and quantitation is 0.161 and 0.538 mg mL −1 .The recovery was 101.48% with a relative standard deviation #3.265% (Scheme 49).

Synthesis of imidazo-pyrimidine carbaldehyde
Imidazo-pyrimidine 85 is a bicyclic heterocycle with a sixmembered pyrimidine ring joined by a ve-membered imidazole ring having both nucleophilic and electrophilic sites (Fig. 12), exist in different tautomeric forms as shown (Fig. 13).These bicyclic ring systems have been reported to have antibacterial, anti-tumor, anti-analgesic, anti-viral and antidepressant activities in literature (Fig. 14).
Initially, the formation of an iminium salt (1) from V. H. reagent takes place.Subsequently, the imidazole-pyrimidine ring (13) partakes in a nucleophilic attack on the iminium salt (1) thereby generating an intermediate (14).The hydrolytic workup of this intermediate (14) culminates in the formylation of imidazo-pyrimidine ring (15).The intricate resonanceenhanced nature of the iminium species greatly accentuates its reactivity, ensuring the efficacy of the formylation process 86 (Scheme 50).

Synthesis of imidazo-pyridine carbaldehyde
Imidazo-pyridine 87 is a nitrogen containing bicyclic heterocycle with a ve-membered imidazole ring joined by a six-membered pyridine ring including nucleophilic and electrophilic sites for substitution reactions (Fig. 15).The different tautomeric forms have been shown in Fig. 16.In addition to existing chemotherapeutic medicines, a wide range of imidazo-pyridine derivatives have been synthesized as possible anti-cancer, anti-diabetic, anti-tubercular, anti-microbial, anti-viral, anti-inammatory agents (Fig. 17).
Primarily, the combination of V. H. reagent (DMF-POCl 3 ) produces the iminium salt (1).The formation of intermediate  (17) through nucleophilic attack of the imidazo-pyridine ring (16) on the electrophilic iminium salt (1) in a subsequent step takes place, which yielded the formylated product (18) upon hydrolysis.This mechanistic pathway demonstrated the ability of V. H. reagent to introduce a formyl group into the fused heterocyclic imidazo-pyridine hybrids 88 (Scheme 52).
In 2018, Antuf et al. 88  In 2015, Jinfa and group 89 synthesized a series of 3substituted imidazo[1,5-a]pyridine-1-carbaldehyde from imidazo[1,5-a]pyridine derivatives using V. H. reagent (DMF-POCl 3 ) in ice-bath followed by stirring the reaction mixture 80 °C for 2 hours, in good yield.Further imidazo[1,5-a]pyridine derivatives were synthesized by using these carbaldehydes which were utilized in cell imaging, biological probes and energy conversion devices (organic light-emitting diodes, OLEDs, and organic photovoltaics (OPV).These bicyclic rings have attracted a lot of attention due to their utility in N-heterocyclic carbene chemistry and medical signicance connected to medicines (HIV-protease and thromboxane A 2 production inhibitors etc.) (Scheme 54).

Synthesis of pyrazolo-pyridine carbaldehyde
Pyrazolo-pyridine 90 carbaldehyde is a class of isomeric heterocyclic compounds with the molecular formula C 6 H 5 N 3 .It is a bicyclic ring system in which pyridine ring act as nucleophilic site whereas pyrazole ring act as electrophilic site (Fig. 18).Various tautomers of these fused rings have been shown in Fig. 19.These compounds have been known to displayed several medicinal applications i.e., anti-cancer, anti-hepatitis, antagonist etc. (Fig. 20).In an initial step the V. H. reagent (DMF-POCl 3 ) generated an iminium salt (1).The enol (19) of the pyrazolo-pyridine ring attack on iminium salt (1) to form an intermediate (20).The hydrolysis of the intermediate (20) afforded the formylated product (22) subsequently.Further, the intermediate ( 21) reacts with POCl 3 , introducing a chlorine atom in the intermediate (22).Through these orchestrated transformations, formylated as well as chlorinated pyrazolo-pyridines are achieved, showcasing the versatility of the V. H. reagent in functionalizing complex heterocyclic structures 91 (Scheme 55).

Synthesis of indole carbaldehyde
An organic molecule with the chemical formula C 8 H 7 N is called indole containing bicyclic ring system consists of a vemembered pyrrole ring fused to a six-membered benzene ring. 92Because pyrrole ring in indole is more electron rich than the benzene ring, electrophile attack always occurs at vemembered ring in normal circumstances (Fig. 21).The different tautomeric forms of the ring have been demonstrated in Fig. 22.It has been used as therapeutic agents in medicinal chemistry and displayed anti-cancer, anti-oxidant, antirheumatoid and anti-HIV activities etc. (Fig. 23).
The proposed mechanism involves a series of interconnected reactions, starting from the addition of ( 23) to iminium salt (1),

Synthesis of thieno-pyridine carbaldehyde
Thieno-pyridine 96 is a bicyclic compound with two fused rings, pyridine ring act as nucleophilic site whereas thiophene ring act as electrophilic site (Fig. 24).The tautomeric structures of these carbaldehyde have been shown in Fig. 25.Various drugs bearing these moieties are used to cure anxiety, depression, bacterial infection, inammation, leishmaniasis, malaria and autoimmune disorders (Fig. 26).
The chlorination of a thieno-pyridine ring with the V. H. reagent involves the activation of N,N-dimethylformamide (DMF) by phosphorus oxychloride (POCl 3 ).The methyl group, depicted active enolizable proton in its mesomeric form (28).The resulting C]C bond of the enol form ( 28) is poised for attack V. H. reagent (1) by forming intermediate (29).The chloride ion then replaces a hydroxy group, forming a resonance stabilized intermediate (30).Further, the lone pair of the nitrogen atom attacks on the electrophilic carbon to form 6membered ring during cyclization with the removal of dimethyl amine group for the chlorination of thieno-pyridine ring ( 31    In 2017, Abdelwahab et al. 98 also synthesized few 4-chloro-3formylthieno [2,3-b]pyridine from N-protected N-(3acetylthiophen-2-yl)acetamide using V. H. reagent (12 equivalent) by stirring the reaction mixture at 65 °C for 4 to 5 hours, in moderate to excellent yield.While at higher temperatures (100 °C) using six equivalent of V. H. reagent, only the formylation of N-(3-acetylthiophen-2-yl)acetamide was reported.Modulation of the reaction parameters led to the generation of unformylated derivatives in superior yield as compared to the reaction involving aminothiophene devoid of protective groups (Scheme 63).

Synthesis of miscellaneous compounds
In 2018, Goncalves and group 99  In 2005, Dong and group 102 synthesized some a-chlorovinyl ketene dithioacetals from oxo ketene dithioacetals using V. H. reagent at −5 °C for 10 to 15 minutes followed by stirring the reaction mixture up to 50 °C for 3-20 hours, in good to excellent yield.The resulting compounds were used as precursors for the synthesis of a-ethynyl ketene dithioacetals.It is evident that electron-donating groups in proximity to the carbonyl exhibit an activating inuence on carbonyl compounds, thereby facilitating the V. H. reaction.On the other hand, strong electronwithdrawing substituents at R 1 in the substrate did not support the V. H. reaction (Scheme 67).
In 2017, Chami and group 103 synthesized 4-chloro-1H-pyrazolo [3,4-d]pyrimidine from 1H-pyrazolo [3,4-d]pyrimidin-4-one using V. H. reagent under reux condition for 30 minutes, in good yield.The resulting compound was screened to analyzed the morphology of steel surface using corrosion monitoring methods.Potentiodynamic polarization curves were also showed potential as corrosion inhibitor of steel.The study relieved that increasing the concentration of inhibitor leads to drop in corrosion current density and an increase in inhibition efficacy (h Tafel %), implying that inhibitor molecules adsorbed at the surface of mild steel to form a protective layer (Scheme 68).i.e., POCl 3 /DMF or SOCl 2 /DMF was used as eco-friendly catalyst for efficient transesterication of keto-esters with various alcohols.The rened green V. H. adducts were found to be superior in contrast to classical V. H. reagent.The reaction time was further diminished and yield was enhanced when ultrasonic and microwave-assisted conditions were employed.The established methodologies facilitated expeditious access to a wide range of esters while circumventing the necessity for excessive quantities of the respective alcohols, oen employed as solvents.Notably, the catalysts employed in this study, namely TCCA, TCTA and DMF are characterized by their costeffectiveness and straightforward implementation, as they are readily available and routinely utilized as laboratory chemicals (Scheme 71).
Additionally, coumarin derivatives were also used as precursors for the production of optoelectronics devices (Scheme 72).
In 2017, Gao et al. 109 synthesized 3-(dicyanomethylidene)indan-1-one using V. H. reagent at 0 °C for 30 minutes followed by stirring the reaction mixture at room temperature for 3 hours.The reaction mixture was further stirred at 85 °C for 12 hours in dichloroethane.This carbaldehyde acted as excellent precursors for the synthesis of thieno [3,2-b]thiophene derivatives.The resulting compound was produced in excellent yield and used in organic solar cells (OSCs) having power conversion efficiencies (PCEs) over 10% (Scheme 74).

Conclusion
In this review, we highlighted the versatility of the Vilsmeier-Haack reagent in facilitating the formation of various ve, six and fused heterocycles demonstrating its utility as a powerful tool for chemical synthesis.These synthetic approaches have not only expanded the scope of accessible heterocyclic compounds but have also enabled the rapid generation of structurally diverse molecules, offering valuable opportunities for drug discovery and development.This brief report will help researchers to explore the synthetic potential of these underutilized scaffolds and will stimulate research in this area to develop newer molecules with biological signicance to be used as future drug.
etc. Priyanka Rani was born in Bhiwani district, Haryana, India.She received her BSc degree in 2015 from Maharshi Dayanand University, Rohtak, and her M.Sc degree in 2017 from Baba Mastnath University, Rohtak.Now she is continuing her study at Chaudhary Bansi Lal University with Dr Mayank Kinger, Associate Professor, Chaudhary Bansi Lal University, Bhiwani, India conducting research work.Her current research interest focuses on ve or sixmembered heterocycles with pharmaceutical potential such as anti-diabetic, anti-anxiety, anti-malarial, anti-inammatory, antifungal activity etc. Deepak Kumar was born in the small village of Saniana of District Fatehabad of Haryana State and obtained his early education from the village.He obtained his BSc in 2004 from CRM Jat (PG) College, Hisar and his MSc in 2006 from Kurukshetra University, Kurukshetra, India.He then joined Jubilant Chemsys Ltd, Noida, as Research Associate and worked there for 2 years from 2006 to 2008.Then, he moved back to Kurukshetra University and Joined the research group of Professor Om Prakash for his PhD studies.He submitted his PhD thesis in 2012 and defended in 2013.He joined GDC Memorial College, Bahal, Bhiwani in 2012 and worked as Assistant Professor for 3 years.In 2015, he joined Chaudhary Bansi Lal University, Haryana as Assistant Professor and is working on the reactivity of hypervalent iodine reagents under different reaction conditions and their importance in different elds of science.
°C for 10 minutes.In MW condition, cyclization of compound (E)-2-(2-(1-phenylethylidene)hydrazinyl)benzo[d] thiazole afforded the enhancement of reaction rate and yielded the compound 1-(benzo[d]thiazol-2-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde from 65% to 83% yield in comparison to thermal condition.The efficient reaction conditions were optimized by performing a series of experiments under varying solvents which revealed in excellent yield of the expected product in 10 minutes when carried out in DMF.

Fig. 5 Scheme 1 Scheme 2
Fig. 5 Some pyrazole-based drugs available in the market.

Fig. 11
Fig. 11 Quinoline based drugs available in the market.

Fig. 23
Fig. 23 Indole based drugs available in the market.