Haack Reagent Research Articles

Near-infrared fluorescent probes for non-invasive, real-time, and dual-color in vivo NIR-II imaging

Multiplexed fluorescence imaging is mainly applied to cellular imaging. However, the application of an analogous technique to mammals remains challenging due to the presence of substantial scattering and autofluorescence in biological tissues in the visible (350–700 nm) and near-infrared I region (NIR-I, 700–900 nm). Herein, we report multiplexing excitation and single-channel detection in the near-infrared II region (NIR-II) with two fluorescent probes for dual-color imaging in vivo. The first one, FNIR-1090 was constructed on Pr-1099 derivative by attaching with 1-Ethylpiperazine through the SRN1 displacement reaction. The second one, IR-765 was synthesized by a one-step reaction between the Vilsmeier–Haack reagent with 2-(3,5,5-trimethylcyclohex-2-enylidene) malononitrile (TEMO). It is noteworthy that the absorption spectrum of FNIR-1090 is almost completely separated from that of IR-765, which facilitates dual-color in vivo imaging. The two dyes can be used for high-contrast dual-channel vivo imaging of different tissues. All these prominent performances show the great promise of FNIR-1090 and IR-765 in non-invasive, real-time, and dual-color NIR-II imaging (>900 nm) in vivo.

Synthetic Utility of the Vilsmeier–Haack Reagent in Organic Synthesis

AbstractThe Vilsmeier–Haack reaction has historically been a topic of significant interest to organic chemists, and it continues to attract considerable attention. The reaction itself provides a facile route towards a large number of aromatic and heteroaromatic systems. The Vilsmeier–Haack reagent, generated from amides and halides, is found to be very important in organic synthesis. This account highlights recent developments in the synthetic utility of the Vilsmeier–Haack reagent.1 Introduction2 Formylation3 Formylation and Chlorination4 Formylation and Acetylation5 Chlorination6 ortho-Formylation7 Miscellaneous8 Conclusions

Convenient and highly efficient microwave-assisted synthesis of 2-Arylimidazo[1,2-a]pyrimidine-3-carbaldehydes in glycerol

A simple and highly efficient method adopted for the synthesis of 2-Arylimidazo[1,2-a]pyrimidine-3-carbaldehyde from reaction of 2-phenylimidazo[1,2-a]pyrimidines, with (Vilsmeier–Haack reagent) in the presence of glycerol as a green reaction medium under microwave irradiation at 400 watt, at 90 °C. Mild reaction conditions, high yield, short reaction time, a clean reaction profile, avoiding toxic catalysts, hazardous organic solvents, and less waste materials are the advantages over the previously adopted method.

Design, synthesis, anticancer evaluation and docking studies of novel 2-(1-isonicotinoyl-3-phenyl-1H-pyrazol-4-yl)-3-phenylthiazolidin-4-one derivatives as Aurora-A kinase inhibitors

IntroductionAurora-A kinase is associated with the Aurora kinase family which has been considered a striking anticancer target for the treatment of human cancers.ObjectiveTo design, synthesize, anticancer evaluation, and docking studies of novel 2-(1-isonicotinoyl-3-phenyl-1H-pyrazol-4-yl)-3-phenylthiazolidin-4-one derivatives as Aurora-A Kinase inhibitors.MethodA total of 21 Pyrazole derivatives P (1–21) were synthesized by using the Vilsmeier Haack reagent which was characterized by FT-IR, 1H NMR, 13C NMR, and Mass spectroscopy. The synthesized derivatives were evaluated for their potential in vitro anticancer activity by MTT assay and Aurora-A kinase inhibition assay.ResultsThe cytotoxicity assay (MTT assay) showed that compound P-6 exhibited potent cytotoxicity (IC50 = 0.37–0.44 μM) against two cancer (HCT 116 and MCF-7) cell lines, which were comparable to the standard compound, VX-680. Compound P-6 also showed inhibition of Aurora-A kinase with an IC50 value of 0.11 ± 0.03 µM. A Docking study was done to compound P-6 and P-20 into the active site of Aurora A kinase, in order to get the probable binding model for further study.ConclusionA series of 21 novel pyrazole derivatives P(1–21) were designed, synthesized, in vitro anticancer evaluation, and docking studies for Aurora A kinase inhibition. The results established that P-6 is a prospective aspirant for the development of anticancer agents targeting Aurora-A kinase.

Designed new mesogens via Vilsmeier–Haack reagent: synthesis and phase transition study

ABSTRACT A new four series of 2,2′-([1,1′- phenyl or biphenyl]-4,4′-diylbis(azanediyl)) bis(N′-((E)-1-(4-alkoxyphenyl) ethylidene) acetohydrazide) [V-XI]a,b and 1,1′-(2,2′-([1,1′- phenyl or biphenyl]-4,4′-diyl bis(azanediyl)) bis- (acetyl)) bis(3-(4-ethoxyphenyl)-1H-pyrazole-4-carbalde hyde) [XII-XVIII]a,b have been synthesized by varying terminal lateral alkoxy chain length (n = 1–3, 5–8), central linkage group (phenyl or biphenyl) and induced pyrazole heterocyclic ring in the main chain. The last two series were synthesized by the cyclization of substituted acetophenone hydrazones with Vilsmeier–Haack reagent (DMF/POCl3) to produce 4-formylpyrazole derivatives. The chemical structures of the synthesized compounds were examined by elemental analysis, FTIR and 1H-NMR. The results are in agreement with the considered molecular structure. The liquid crystalline behaviors were studied by using hot-stage optical polarizing microscopy (OPM) and differential scanning calorimetry (DSC). The correlation between the molecular structures and mesomorphic behavior and transition temperatures was discussed.

1,3,4-Trisubstituted Pyrazoles: Synthesis, Antimicrobial Evaluation, and Time Resolved Studies

In this article, an efficient and practicable synthesis of 1,3,4-trisubstituted pyrazoles with an acyl functionality attached on the 4-position of the pyrazole scaffolds is reported. The precursor 4-cyanopyrazoles used for the fabrication of target compounds were synthesized from 4-formylpyrazoles via oxime formation followed by reaction with Vilsmeier–Haack reagent. The reaction of 4-cyanopyrazoles with various Grignard reagents afforded the corresponding 1,3,4-trisubstituted pyrazoles in 71–88% yield. The operational simplicity, economical starting materials, and high efficiency compared to reported methods are the advantages of this approach. All the pyrazole derivatives have been screened for antimicrobial activity and some of the derivatives exhibit significant activity against bacterial and fungal isolates. Further, time resolved photoluminescence studies for 5d, 5h, & 5o were carried out using pulsed nitrogen laser as the source with a pulse width of few nanoseconds and wavelength of 337 nm. The spectrum was observed in microsecond time domain in all the cases, however, fluorescent lifetime is found to higher in 5d & 5h.

Reactions of Polyfluoroaromatic Organozinc Compounds with Oxalyl Chloride in DMF. Synthesis of Polyfluoroaromatic Aldehydes

The reaction of polyfluoroaromatic organozinc compounds with oxalyl chloride in DMF proceeds involving the Vilsmeier–Haack reagent with the formation of polyfluoroaromatic aldehydes as the major products. The use of CuI makes it possible to increase the yield of the target aldehydes.

4-(3-Phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)thieno[3,2-d]pyrimidine

A new hybrid compound, 4-(3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)thieno[3,2-d]pyrimidine 3, with promising biological activity was efficiently synthesized by the reaction of 3-phenyl-1-(thieno[3,2-d]pyrimidin-4-yl)-1H-pyrazol-5-amine with Vilsmeier–Haack reagent and subsequent treatment with ammonium carbonate. The structure of the synthesized compound was fully characterized by 1H-, 13C-NMR, IR spectroscopy, mass-spectrometry and elemental analysis.

Some Features of the Reaction of 6-Methyl-2S-substituted Pyrimidin-4-ols with the Vilsmeier–Haack Reagent

Formylation of 6-methyl-2S-substituted pyrimidin-4-ols under the conditions of the Vilsmeier–Haack reaction leads to the formation of nucleophilic substitution products of the hydroxyl group. The formation of the expected formylation products does not occur.

Novel Approach for Rapid and Efficient Synthesis of 2‐(3‐(4‐Aryl)‐1‐isonicotinoyl‐4,5‐dihydro‐1H‐pyrazol‐4‐yl)‐3‐phenylthiazolidin‐4‐one Derivatives and Screened Their Antimicrobial Activity

A series of compounds, viz. 2‐(3‐(4‐aryl)‐1‐isonicotinoyl‐4,5‐dihydro‐1H‐pyrazol‐4‐yl)‐3‐phenylthiazolidin‐4‐one 4 (a–n), have been synthesized by reaction of 3 (a–n) with thioglycolic acid in the presence of zinc chloride. Compounds 3 (a–n) have been synthesized by amination of formylated pyrazoles 2 (A–B), which were synthesized by formylation of 1 (A–B) by Vilsmeier–Haack reagent (POCl3/DMF). Compounds 1 (A–B) were synthesized by condensation of hydrazide and substituted acetophenones under conventional method and microwave irradiation method. These compounds were identified on the basis of melting point range, Rf values, infrared, 1H NMR, and mass spectral analysis. These compounds were evaluated for their in vitro antimicrobial activity, and their minimum inhibitory concentration was determined. Among them, compound 4b and compound 4l possess appreciable antimicrobial and antifungal activities. Antibacterial activity results showed that compounds containing electron‐withdrawing groups were more active than compounds containing electron‐releasing groups.

Synthesis, Characterization, Molecular Docking, and Antimicrobial Activity of New Arylidene-Substituted Imidazoles

The title compounds are synthesized by condensation of 2-[4-(arylidene)-5-oxo-4, 5-dihydrooxazol-2-yl]phenylacetate with aromatic amines in presence of the Vilsemeier Haack reagent. Structures of all compounds are elucidated from 1H and 13C NMR, IR, and mass spectra. The compounds are tested for their antibacterial activity. Molecular docking study is focused on the relative orientation and nature of bonding between imidazoles and bacterial protein.

Formamide Catalysis Facilitates the Transformation of Aldehydes into Geminal Dichlorides

Herein, a novel method for the transformation of aldehydes into geminal dichlorides based on phthaloyl chloride as reagent and N-formylpyrrolidine as Lewis base catalyst is disclosed. Given the mild reaction conditions, the current protocol is distinguished by high levels of functional group compatibility and scalability and is operationally simple. The in situ formation of a Vilsmeier Haack reagent type intermediate is likely to be essential for this organocatalytic nucleophilic substitution reaction.

Microwave Assisted Vilsmeier-Haack Reaction on Substituted Cyclohexanone Hydrazones: Synthesis of Novel 4,5,6,7-Tetrahydroindazole Derivatives

Vilsmeier-Haack reaction is one of the most important chemical reactions used for formylation of electron-rich arens. Even though Vilsmeier-Haack reaction was studied on a wide variety of hydrazones of enolizable ketones, literature lacks the examples of the use of 4-substituted cyclohexanones as a substrate. The cyclization potential of hydrazones of cyclic keto compounds is still interested topic of investigation. In the present study, the reaction of various hydrazines with 4-substituted cyclohexanones was proceeded and the resulted hydrazones in crude form were treated with Vilsmeier- Haack reagent using both conventional as well as microwave methods. The reaction of phenyl hydrazine with 4-phenylcyclohexanone yielded the corresponding tetrahydro-1H-carbazole instead of hydrazone during solvent evaporation at 40ºC. By keeping the temperature of water bath to 0ºC, the corresponding hydrazone was isolated in crude form which was immediate treated with POCl3/DMF for 10 min at 90ºC using microwave irradiation method afforded novel 4,5,6,7-tetrahydroindazole derivative. Using this optimized condition, the substrate scope for the synthesis of tetrahydroindazole derivatives was explored and synthesized total 6 final compounds. The microwave assisted synthesis of tetrahydroindazoles from 4-substituted cyclohexanones has been reported for the first time under mild conditions in good yield. Easy work up procedure, high yielding, shortened reaction times, clean and ecofriendly are the main advantages of this protocol.

Vilsmeier–Haack reagent mediated synthetic transformations with an immobilized iridium complex photoredox catalyst

The synthesis of amides, nitriles, and anhydrides via reactions under the action of the visible-light-driven in situ generated Vilsmeier–Haack reagent from CBr4 in DMF.

Vilsmeier-Haack reaction of 7-acetyl-2-arylindoles: a convenient method for the synthesis of 6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-1,5-dicarbaldehydes.

A simple and efficient method for the one-pot synthesis of novel 6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-1,5-dicarbaldehydes via the Vilsmeier-Haack reaction of the corresponding 7-acetyl-2-arylindoles has been developed. The mechanism of this reaction is envisaged to involve initial C-3 formylation and subsequent diformylation at the acetyl group with the excess Vilsmeier-Haack reagent followed by heteroannulation of the six-membered ring with concomitant extrusion of dimethylamine to afford the 1,2,5,8-tetrasubstituted pyrroloquinolinones. The highlight of this method is the construction of carbon-carbon and carbon-nitrogen bonds in a single-pot operation to afford polycarbo-substituted pyrroloquinolinones.

A facile approach for the synthesis of novel xanthene derivatives with Vilsmeier–Haack reagent

A series of new derivatives of formylxanthenes have been synthesized via the reaction of substituted 1,3-benzoxazines with Vilsmeier–Haack reagent. It has been shown that 1,3-benzoxazines unsubstituted in the aromatic part and 6-bromo-1,3-benzoxazines are rearranged into xanthene derivatives under heating at 80°C for 1.5 h. Substitution at the C-8 position of 1,3-benzoxazines, especially with electronegative groups significantly inhibits the reaction. So, the presence of iodine atoms at the C-6 and C-8 positions leads to increase in reaction time up to 8 h, the presence of bromine atom in the C-8 position requires heating up to 100°C for 11 h.

A novel synthetic approach for the synthesis of pyrano[3,2-c] quinolone-3carbaldehydes by using modified Vilsmeier Haack reaction, as potent antimicrobial agents

This research work is about the synthesis of pyranoquinolone-3carbaldehydes, heterocyclic compounds which were constructed by modifying Vilsmeier-Haack reaction. A leading approach towards green chemistry and successful methodology was devised during this research project for the synthesis of various pyranoquinolone-3-carbaldehydes at low temperature. Some workers reported the synthesis of chromones and chloroquinoline-3carbaldehydes. Interesting aspect of the present work was to successfully utilize two methodologies during a single reaction (one to cyclize a pyran ring and second to insert formyl group) by manipulating the different functional groups attached to the reactants and to construct the desired molecules. In some works, cited during the formylation reaction by using Vilsmeier Haack reagent, halogenated products were reported while in this synthetic study the final products were formylated but nonhalogenated. This methodology is a milestone for the construction of an aldehyde functional group on some parent moieties. The reaction is an example of one pot synthesis. All synthesized compounds were found having several pharmacological characteristics. These derivatives were characterized by FTIR, 1HNMR, EIMS and elemental (C, H and N) analyses; confirming the synthesis of the labelled products. The reactants used in this research project were synthesized by Gould Jacobs reaction prepared during our last research project as cited [26]. The antibacterial activity of ligands and metal complexes was determined by disc diffusion method using Bacillus subtilis, Escherichia coli, and Staphylococcus aureus and got excellent results.

Ultrasonic and Microwave effects on the Benzamide/Sulfuryl Chloride mediated benzoylation of Benzene derivatives under Vilsmeier-Haack conditions

Benzamide/ Sulfuryl Chloride (SO2Cl2) reagent has been developed as a Vilsmeier- Haack(VH) reagent for benzoylation of aromatic compounds by using the conventional and ultrasonic sonication (US), and microwave (MW) conditions. Benzoylation is much more competent and faster than the analogous VH ((Benzamide/ POCl3) or (Benzamide/ SOCl2)) reagents and afforded benzoyl derivatives in good yields. Reaction times are moderately less than those observed with [Benzamide/ POCl3] and (Benzamide/ SOCl2) reagents. Reaction times are far less in microwave assisted (MWAR) reactions than ultrasonically assisted (USAS) reactions , which in turn are less than the conventional method with a decreasing trend: MWAR (seconds) << Sonication (minutes) << conventional (hrs). The highly remarkable rate accelerations in MW assisted reactions are attributed to the bulk activation of the molecules; while US assisted reactions could be accounted for cavitation effects.

Unusual formation of (E)-11-(amino-methyl-ene)-8,9,10,11-tetra-hydro-pyrido[2',3':4,5]pyrimido[1,2-a]azepin-5(7H)-one and its crystal structure.

Selective C-formyl-ation of 8,9,10,11-tetra-hydro-pyrido[2',3':4,5]pyrimido[1,2-a]-azepin-5(7H)-one has been studied for the first time. It was revealed that formyl-ation proceeds by the formation of an inter-mediate salt, which due to the re-amination process on treatment with aqueous ammonia transformed into the corresponding (E)-11-(amino-methyl-ene)-8,9,10,11-tetra-hydro-pyrido[2',3':4,5]-pyrimido[1,2-a]azepin-5(7H)-one, C13H14N4O, as an E-isomer. Formyl-ation was carried out by Vilsmeier-Haack reagent and the structure of the synthesized compound was confirmed by X-ray structural analysis, spectroscopic and LC-MS methods. In the mol-ecule, the seven-membered penta-methyl-ene ring adopts a twist-boat conformation.

Targeted Synthesis of 4-Chloro-3-formylthieno[2,3-b]pyridine and/or 4-Chlorothieno[2,3-b]pyridine by Reaction between N-Protected 3-Acetyl-2-aminothiophenes and Vilsmeier–Haack Reagent

Formylated chlorothieno[2,3-b]pyridine derivatives were synthesized by reaction between N-protected 3-acetyl-2-aminothiophenes and Vilsmeier–Haack reagent under classical conditions. These products were not accessible without N-protection of the starting materials or by reaction between the reagent and 4-chlorothieno[2,3-b]pyridine under any conditions. The conditions of the reaction could be altered to produce unformylated derivatives in better yields than reaction with unprotected aminothiophene.