Vilsmeier Reagent Research Articles

Recent Routes in Synthesis and Biological Activity of Pyrimido[4,5-b] Quinoline Derivatives: A Review (Part II)

The synthesis of organic molecules has been a tremendous and rapid advance in the recent decade to obtain high biological and pharmacological activities. In this review, the organic synthesis of pyrimido[4,5-b]quinoline derivatives is considered an alternative method to traditional procedures for treating many diseases that affect humans. Also, by transferring electrons, stereoselective syntheses occur via organic reactions in various unnatural and natural conditions at room temperature and normal pressure. We found that the structure of pyrimido[4,5-b]quinoline derivatives was formed by substrates, bases, electrophiles, and low-level and highly stable reagents that can be broadly applied to synthesize more heterocycles. These reagents include: 2- nitrobenzaldehyde; 3-(benzyloxy)-4-methoxy-2-nitrobenzaldehyde; 4,5-dimethoxy-2- nitrobenzaldehyde; 2-aminobenzaldehyde; 2-aminoquinoline-3-carboxamide; 2-chloroquinoline3-carbaldehyde; 2-bromobenzaldehyde; 2-chloroquinoline-3-carbonitrile; 2-chloroquinoline-3- carboxylic acid; aniline; phenyl-methanamine; amino-quinoline-3-carboxylic acid /aminoquinoline-carbonitrile; amino-6,7-dimethoxy-quinoline-3-carbonitrile; amino-oxolo [4,5- g]quinolin-carboxamide; 3-(aminomethyl) quinolin-2-amine; 4-aminobenzo[d][1,3] dioxole-5- carbaldehyde; thiourea; ethyl 3-oxo-butanoate; 2-cyano-acetamide; 2-(bis (methylthio) methylene) malononitrile; ethyl 3,3-diamino-2-cyanoacrylate; naphthalene-1,4-dione; and N-carbamoyl-2- cyanoacetamide derivatives. The prepared pyrimido[4,5-b]quinoline derivatives were described through means of the following chemical reactivity: alkylation, bromination, chlorination, cyclocondensation, cyclization, acylation, oxidation-reduction, dehydration, addition reaction and Vilsmeier-Haack reaction (Vilsmeier reagent).

One‐pot Microwave‐assisted Synthesis of Pyrazolopyrimidines from 5‐Amino‐4‐thiocyanato‐pyrazoles with Vilsmeier Reagent

AbstractA facile one‐pot microwave‐assisted synthesis of pyrazolopyrimidines and pyrazolothiazoles was developed by reacting 5‐amino‐4‐thiocyanato‐pyrazoles with Vilsmeier Reagent (PBr3/foramide). The reaction gave the corresponding pyrazolopyrimidines as major products in good yields (61–85 %) and pyrazolothiazoles as minor products (11–23 % yields). The plausible reaction mechanism was proposed to account for the transformation of pyrazolopyrimidines and pyrazolothiazoles through two paths A and B. In path A, the reaction leading to the formation of pyrazolopyrimidines proceeded through four sequential steps, including acidic catalyzed cascade dethiocyanation/cyclization, Vilsmeier reaction, ring expansion, and deamination. The formation of the pyrazolothiazole in path B was caused by the nucleophilic heterocyclization reaction involving the sulfur nucleophilic reaction of thiocyanate (R−SC≡N) and the departure of a cyanamide. Based on the experimental results, we observed that the path A for the formation of pyrazolopyrimidines was more favorable.

Flow Photo-on-Demand Synthesis of Vilsmeier Reagent and Acyl Chlorides from Chloroform and Its Applications to Continuous Flow Synthesis of Carbonyl Compounds

Flow Photo-on-Demand Synthesis of Vilsmeier Reagent and Acyl Chlorides from Chloroform and Its Applications to Continuous Flow Synthesis of Carbonyl Compounds

Fluorinated Vilsmeier Reagent: TFEDMA‐mediated Synthesis of Aryl‐cyanides and Aryl‐amides via the Activation of Oximes†

AbstractA convenient method for the activation of aryl‐oximes is reported using 1,1,2,2‐tetrafluoro‐N,N‐dimethylethylamine (TFEDMA) as a scalable and efficient reagent. Aryl‐aldoximes led to aryl‐cyanides while aryl‐ketoximes provided aryl‐amides in moderate to excellent yields. The iminium form of TFEDMA acted as a fluorinated version of the well‐known Vilsmeier reagent. Aryl cyanides and aryl amides are valuable synthetic units in natural products and drug candidates. The cyano group is also useful in polymer chemistry for the preparation of photovoltaic cells and LEDs.

New molecular hybrids containing benzimidazole, thiazolidine-2,4-dione and 1,2,4-oxadiazole as EGFR directing cytotoxic agents

Herein, we, synthesized some new molecular hybrids (7a-o) having benzimidazole, thiazolidine-2,4-dione and 1,2,4-oxadiazole scaffolds from the commercially available 1-methyl-1H-benzo [d]imidazole-2-carbaldehyde (1) using two key methodologies such as Knoevenagel condensation and Vilsmeier reagent mediated one-pot synthesis. Further, all the compounds in their μM concentration were screened for their in vitro cytotoxic activity against three human cancer cell lines which includes MCF-7, A-549 and HepG2. Among all, the compound 7n exhibited superior activity against all the cell lines as compared to standard drug erlotinib. Besides, the compounds 7d, 7e and 7f showed superior activity against MCF-7 and most promising activity against A-549 and HepG2 when compared with the positive control. As well, the tyrosine kinase EGFR inhibitory activity for the potent compounds 7d, 7e, 7f and 7n, revealed that the compounds 7e and 7n displayed nearly double potency as compared to the erlotinib drug. The molecular docking studies of active compounds 7d, 7e, 7f and 7n on EGFR target were also conducted and the results were found to be covenant with the corresponding IC50 values.

Synthesis, characterization and application of chitosan conjugated heterocyclic compounds

Derivatives of formyl pyrazole were synthesized by the reaction of acetophenone, 4-methyl acetophenone, 3-acetyl furan, 3-acetyl thiophen and phenyl hydrazine derivatives. The product was treated with Vilsmeier reagent producing different formyl pyrazole derivatives which were characterized by FT-IR, 1HNMR, Elemental analysis and Mass spectroscopy. The formyl pyrazole derivatives were reacted with chitosan to produce chitosan/ pyrazole Schiff base. These Schiff bases were characterized by FT-IR and TGA.The antimicrobial activity of chitosan/ pyrazol Schiff base (CSB) was evaluated against Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus), gram negative bacterium (Escherichia coli) and fungus (Aspergillus niger). Results indicated agood inhibitory activity for CSB-14 when tested against B.cereus that gave inhibition zone of 7.5 ± 0.6 (mm), however CSB-18 gave a pronounced inhibitory activity against S. aureus and recorded 25 ± 2.0 (mm). All synthesized derivatives have no inhibitory activity against Gram negative E. coli. CSB-14, and CSB-15 exhibited inhibitory activity against tested A. niger that was used as a fungal model which gave 19 ± 0.9 and 18 ± 1.0 inhibition zone (mm) respectively. Thus, these results showed that, functionalization of chitosan with the hetero-cyclic compounds created biological activities of the synthesized derivatives; hence the synthesized pyrazole derivatives have not recorded any inhibitory activity before its immobilization onto chitosan.

Molecular Docking, ADME Studies, Synthesis, and Anti-oxidant Activity of Novel Quinazoline-4(3H)-one Derivatives

Background Free radicals are linked to numerous human diseases. Free radicals can be neutralised by antioxidants thereby reducing their negative effects. We sought to learn more about the antioxidant and free radical scavenging abilities of quinazoline derivatives in this study.Aim of the study Drug discovery and development is a time-consuming interdisciplinary and expensive process. Advances in computational procedures have empowered in silico routines and specifically structure-based drug design technique to accelerate new target choice for the improvement of lead compounds. Hence the present work aimed to identify the potent quinazolinone compounds for synthesis.Methodology The synthesis was carried out from the reaction of anthranilic acid and primary aromatic amines with Vilsmeier reagent DMFPOCl3 . Five derivatives which obeyed rule of five having desired physio-chemical properties were synthesized PDB code 6DE4. The reaction occurred in few minutes under microwave irradiation providing good yields. The synthesized compounds were isolated recrystallised by using suitable solvents purified by Thin Layer Chromatography TLC and characterized by Fourier-transform infrared spectroscopy FT-IR Proton-Nuclear Magnetic Resonance 1 H NMR and mass spectroscopy.Results All the synthesized compounds 3a 4a 8b 9b 10b were evaluated for their anti-oxidant activities by 22-diphenyl-1-picrylhydrazyl DPPH Hydrogen peroxide H2 O2 assays. All of them showed significant anti-antioxidant activity with 8b exhibiting the maximum activity compared to others.Conclusion On comparison with standard ascorbic acid quinazolinone derivatives were found to possess effective in vitro antioxidant activity. These quinazoline analogues could be considered as useful templates for further development to obtain more potent antioxidant activity.nbsp

Transformation of tert‐Butyl Amide Directing Groups to Nitriles in Iridium‐Catalyzed C−H Bond Functionalizations

AbstractTo overcome limitations of the directing group in IrCp* catalysis for C−H functionalization, we developed a directing group transformation strategy that was applied after obtaining the desired products. Well‐established Ir‐catalyzed alkenylation, alkylation, and arylation reactions were performed under mild conditions, and then the stable coordinating amide groups were efficiently converted to versatile nitrile groups by in situ treatment with Vilsmeier reagent at room temperature. Whereas the conversion of primary amides has been extensively studied with modified Appel protocol, nitrile formation from secondary amides is very limited. Various ortho‐functionalized benzonitrile derivatives (31 examples) were synthesized using this simple methodology, and the subsequent oxidative cyclization of an ortho‐alkenylated product was investigated to demonstrate the synthetic utility of this strategy. This simple and versatile methodology should be available under various transition metal catalysis with stable amide directing groups.

Synthesis and Anticonvulsant activity of new 5-((1-(2-(4-substituted phenacyl bromide)-2-oxoethyl)-2-phenyl-1H-indol-3yl) methylene) pyrimidine-2, 4, 6(1H, 3H, 5H)-trione Derivatives

In the current scenario we have plant to study to synthesize novel indole derivatives (4a-d) and (5a-b) which have the target activity like anti-convulsion and anti microbial etc. In the primary phase, we synthesized 2-phenyl-1H-indole reacted with Phosphorus oxychloride and N, N’-dimethylformamide by using vilsmeier reagent formylation of a new compound 2-phenylindole-3-carbaldehyde (2). The 2-phenylindole-3-carbaldehyde was reacted with substituted phenacyl bromide, K2CO3 and TBAB (Tetra butyl ammonium bromide) into the presence of N, N’-dimethylformamide to gives [1-(2-(4-substituted phenacyl bromide)-2-oxoethyl)-2-phenylindole-3-carbaldehyde (3a-d). The compound [1-(2-(4- substituted phenacyl bromide)-2-oxo-ethyl)-2-phenylindole-3-carbaldehyde was permitted to mixed with various substituted phenacyl bromide gives corresponding indole derivatives. The indole derivatives (3a-d) were reacted with barbituric acid and thiobarbituric acid dissolved into the methanol at reflux for 4h to gives afforded compounds (4a-d) and (5a-b). The final indole barbituric derivatives (4a-d) and (5a-b) were synthesized from substituted phenacyl bromide by the react with methanol and recrystalized from ethanol. The last compound has been completed on the basis of spectra FT-IR and 1H NMR. All the value of FT-IR, 1H NMR, Solubility and TLC were considered to be prominent. The pharmacological screening through ear electrode induced current 50mA for 0.2 seconds in electro-convulsiometer for anticonvulsant activity. The synthesize compounds were establish to be 4b, 4c, 4d, and 5a. The compound 4c and 5a were established to be the most potent compound through compare to standard drugs phenytoin sodium.

Photo-on-Demand Synthesis of Vilsmeier Reagents with Chloroform and Their Applications to One-Pot Organic Syntheses.

The Vilsmeier reagent (VR), first reported a century ago, is a versatile reagent in a variety of organic reactions. It is used extensively in formylation reactions. However, the synthesis of VR generally requires highly toxic and corrosive reagents such as POCl3, SOCl2, or COCl2. In this study, we found that VR is readily obtained from a CHCl3 solution containing N,N-dimethylformamide or N,N-dimethylacetamide upon photo-irradiation under O2 bubbling. The corresponding Vilsmeier reagents were obtained in high yields with the generation of gaseous HCl and CO2 as byproducts to allow their isolations as crystalline solid products amenable to analysis by X-ray crystallography. With the advantage of using CHCl3, which bifunctionally serves as a reactant and a solvent, this photo-on-demand VR synthesis is available for one-pot syntheses of aldehydes, acid chlorides, formates, ketones, esters, and amides.

An Effective Route to Dithieno[3,2-b:2′,3′-d]thiophene-Based Hexaheteroacenes

AbstractA series of 12H-[1]benzo[4′′,5′′]thieno[2′′,3′′:4′,5′]thieno[2′,3′:4,5]thieno[3,2-b]indoles were efficiently prepared in three steps starting from available benzo[b]thieno[2,3-d]thiophen-3(2H)-ones. These fused ketones were treated with the Vilsmeier reagent and hydroxylamine hydrochloride to give the corresponding 3-chlorobenzo[b]thieno[2,3-d]thiophene-2-carbonitriles, which then reacted with methyl sulfanylacetate to form methyl 3-aminobenzo[4′,5′]thieno[2′,3′:4,5]thieno[3,2-b]thiophene-2-carboxylates, in accordance with the Fiesselmann thiophene synthesis protocol. Finally, the desired N,S-heterohexacenes were obtained by conversion of these fused 3-aminothiophene-2-carboxylates into the corresponding 3-aminothiophene intermediates, which acted as synthetic equivalents of thiophen-3(2H)-ones, followed by their acid-promoted reaction with arylhydrazines, in accordance with the Fischer indolization procedure.

Synthesis, Antibacterial, and Molecular Docking Study of Novel 2-Chloro-8-Methoxy-3-Aryl-[1,3] Benzoxazine Derivatives using Vilsmeier Reagent

Reducing of ethyl 4-((2-hydroxy-3-methoxybenzylidene)amino)benzoate (1) afford ethyl 4-((2-hydroxy-3-methoxybenzyl)amino)benzoate (2). Reaction of this compound with Vilsmeier reagent affords novel 2-chloro-[1,3] benzoxazine ring (3). The corresponding acid hydrazide of compound 3 was synthesized from reaction of compound (3) with hydrazine hydrate. Newly series of hydrazones (5a–i) were synthesized from reaction of acid hydrazide with various aryl aldehydes. Antibacterial activity of the hydrazones was secerned utilizing gram-negative and gram-positive bacteria. Compound (5b) and (5c) exhibited significant antibacterial ability against both gram-negative and gram-positive bacteria, while the compounds (5a) showed mild antibacterial activity. Compounds (5d–i) did not display notable activity. The molecular docking of synthesised compounds were tested inside the pocket of bacterial gyrase enzyme target site by using MOE 2015 software, which acts as Adenosine triphosphate (ATP)-binding domain bacterial gyrase enzyme pocket and novobiocin was used as reference.

Mechanistic Understanding of a Robust and Scalable Synthesis of Per(6-deoxy-6-halo)cyclodextrins, Versatile Intermediates for Cyclodextrin Modification

Cyclodextrin (CD) perfunctionalization reactions are challenging to study because they proceed through a number of regioisomeric intermediates, thus warranting creative approaches to understanding the reaction mechanism. Particularly useful perfunctionalization targets are per(6-deoxy-6-halo)cyclodextrins. Their standard synthesis entails selective SN2 halogenation at their primary alcohols using a Vilsmeier reagent, but this requires a strongly basic quench to unmask the Vilsmeier-capped secondary alcohols. Herein we present an alternative and simple acidic hydrolytic quench that utilizes existing HX in the end-of-reaction solution and requires only the addition of water. We performed a detailed mechanistic investigation of the new quench, and a central feature was the use of proton sponge to develop an 1H NMR titration method for HX in organic solvent. This method was used to both quantify and remove HX in the prequenched reaction solution. The HX-free prequenched solution enabled us to (1) identify sensitive intermediates during the quench, (2) quantify all of the reaction byproducts, and (3) determine that HX is critical for hydrolysis. We then studied the halogenation reaction, wherein the new acidic quench facilitated high-throughput experimentation, using mass spectrometry as well as Design of Experiments with automated reaction profiling. Through this, we were able to establish robustness and understand the complex effects of Vilsmeier equivalents and temperature on the reaction outcome.

Synthesis of TFA-protected α-Amino Acid Chloride via a Vilsmeier Reagent for Friedel–Crafts Acylation

α-Amino acid chlorides are reactive coupling agents in amide (peptide) formation. The Vilsmeier reagent ((chloromethylene)dimethylammonium chloride) offers a convenient way to prepare α-amino acid chlorides for peptide synthesis. Its use with N-trifluoracetyl (TFA)-protected isoleucine and allo-isoleucine is described. The 1H-NMR of the α-proton signal offers a convenient way to monitor the chirality retention in the acid chloride forming reaction and subsequent Friedel-Crafts acylation of arenes which result in α-amino acid aryl-ketone with no loss of chirality.

A Vilsmeier Chloroformylation by Continuous Flow Chemistry

Chloroformylation reactions are versatile reactions that allow the introduction of a chlorine atom and an aldehyde group in enolizable ketones, employing the well-known Vilsmeier reagent. However, ...

A Leopard Cannot Change Its Spots: Unexpected Products from the Vilsmeier Reaction on 5,10,15-Tritolylcorrole.

The reaction of 5,10,15-tritolylcorrole with 3-dimethylaminoacrolein (3-DMA) and POCl3 gives a further example of the rebel reactivity of this contracted macrocycle. While no evidence was obtained for the formation of the expected β-acrolein corrole, the inner core substituted N21,N22-3-formylpropylcorrole and the 10-acrolein isocorrole were the reaction products. By increasing the temperature or the amount of the Vilsmeier reagent, the 10-isocorrole became the unique reaction product. The formation of the isocorrole by electrophilic attack of the Vilsmeier reagent to the 10-position of the corrole is unprecedented in the porphyrinoids field and it could pave the way for a novel route to the preparation of stable isocorroles.

Nucleophilic Attack of Azide at Electrophilic Azides: Formation of N6 Units in Hexazene and Aminopentazole Derivatives.

With the help of selective 15N labeling experiments, it has been confirmed that nucleophilic attack of azide at iminium‐activated organic azides leads to short‐lived hexazene intermediates. Such species do not only tend to a cleavage reaction with formation of N‐azido compounds, but also undergo ring closure to generate unprecedented amidino‐functionalized pentazoles. Thus, treatment of the parent Vilsmeier reagent with two equivalents of sodium azide creates an aminopentazole derivative as the main product, which is easily characterized by NMR spectroscopy.

Selective monochlorination of unsymmetrical vicinal diols with chlorinated iminium chlorides

Chlorinated iminium chlorides have been identified to promote the highly efficient and selective mono-chlorination of unsymmetrical vicinal diols. Vilsmeier reagent, namely, (chloromethylene)dimethyliminium chloride, enables highly reactive and regioselective chlorination of 1,2- and 1,3-diols featured one secondary benzylic hydroxy group and one primary aliphatic hydroxy group to give the corresponding 1,2- and 1,3-chlorohydrins. Viehe’s salts (α,α-dichloro iminium salts) exhibit excellent reactivity and good selectivity for vicinal diols to give the corresponding chlorohydrin carbamates via a cyclic intermediate in situ. The chlorination protocols tolerate diverse functional groups, including halogens, naphthalene rings, nitro, and cyano. Moreover, the optical purity of chiral diols could be retained during this chlorination reaction.

Synthesis of Chalcones from Acetone and tetrazole and 2-acetyl naphthalene Assisted by Microwave

In the present study, we understood the total synthesis one chalcone derivative via Claisen-Schmidt condensation of the respective aldehydes and ketones using Microwave assisted irradiation method. In the microwave environment, chemical reactions usually proceed faster and give higher yields with fewer by- products. In the synthesis, a common aldehyde namely tetrazolo {1, 5-a} quinoline-4-carbaldehyde was used while the ketones used were respectively acetone, 2- acetyl Naphthalene. The Chalcone synthesised from Tetrazolo {1, 5-a} quinolone-4-carbaldehyde and acetone was 4-(tetrazolo {1, 5-a} quinoline-4-yl) but -3-en-2-one. The Chalcone synthesised from Tetrazolo {1, 5-a} quinoline-4-carbaldehyde and 2-acetyl Naphthalene was 2E-1-(naphthalene-2-yl)-3-(tetrazolo {1, 5-a} quinolone-4-yl) prop-2-en-1- one. The starting aldehyde was Tetrazolo {1, 5-a} quinoline-4-carbaldehyde necessary for the Claisen-Schmidt condensation was in turn synthesized from Acetanilide which and Vilsmeier reagent (DMF and PoCl3) to produce the intermediate compound 2-chloroquinoline-3-carbaldehyde. This intermediate 2-chloroquinoline-3-carbaldehyde was then treated with sodium azide and acetic acid with ethanol as solvent to produce Tetrazolo {1, 5-a} quinoline-4-carbaldehyde. Structure of the compound were confirmed by spectral data such as IR and 1H-NMR.

Vilsmeier reagent, NaHSe and diclofenac acid chloride: one-pot synthesis of a novel selenoindolinone with potent anticancer activity.

An effective and straightforward synthesis of 3-seleno functionalized indolinone (5) involving Vilsmeier reagent is presented. Likewise, a procedure to achieve lactamization of diclofenac with excellent yields by using hydrides is also ascertained. Compound 5 exhibited impressive growth inhibition in most of the cell lines in an NCI-60 panel, particularly towards resistant breast cancer cells.