Vilsmeier Reagent Research Articles

A convenient one-pot synthesis of (R)-2-amino-3,3,3-trifluoro-2-methyl-N-phenylpropanamide derivatives

A convenient one-pot synthesis of enantiopure (R)-2-amino-3,3,3-trifluoro-2-methyl-N-phenylpropanamide derivatives has been developed. The key step in this synthetic methodology turned out to be the amide formation in which (R)-2-amino-3,3,3-trifluoro-2-methylpropanoic acid hydrochloride was simultaneously protected and activated by Vilsmeier reagent.

An alternative synthesis of pyrimido[4,5-b]quinoline-4-ones via metal-free amination in water and Vilsmeier–Haack cyclization

Two-step synthesis of pyrimido[4,5-b]quinoline-4-ones is described from 2-chloroquinoline-3-carbonitries via amination and cyclization reactions, respectively. The amination reactions proceeded much faster in water via simple SNAr displacement reactions of chlorine. The cyclization reactions using Vilsmeier reagent at 60°C gave the best yield of the products. The isolation of starting compound from the reaction of cyclized product with I2/K2CO3 provided further chemical proof of the structure of the cyclized product. Plausible mechanism for cyclization is proposed.

Eco-friendly synthesis of highly substituted functionalized oxazines by FeCl3/SiO2 nanoparticles

An efficient and modern method for the preparation of amidoalkyl naphthols in the presence of silica nanoparticle-supported ferric chloride under thermal solvent-free conditions is explained. The prepared amidoalkyl naphthols were converted to 1,3-oxazines by Vilsmeier reagent in the presence of FeCl3/SiO2 nanoparticles. This method provides a novel route to synthesis amidoalkyl naphthol and 1,3-oxazine derivatives in terms of good yields, short reaction times, and recyclable catalyst.

Continuous-Flow Preparation and Use of β-Chloro Enals Using the Vilsmeier Reagent

The Vilsmeier reagent is used in the preparation of a wide variety of heterocycles, such as pyrazoles, via formation of β-chloroacrolein intermediates. However, use of this extremely reactive reagent on large scale requires special precautions to avoid potentially dangerous exotherms. This article describes the safe preparation at room temperature of the Vilsmeier reagent under flow conditions for the formation of β-chloroacroleins and 3-formylchromones, as well as the use of these in multistep, continuous flow processes for the syntheses of β-acrylonitriles and polysubstituted pyrazoles.

Synthesis and characterization of novel second-order NLO-chromophores bearing pyrrole as an electron donor group

Two series of novel push–pull 1-(4-(thiophen-2-yl)phenyl)-1H-pyrroles 3–5 were designed to explore the consequence of using different electron accepting moieties linked to the thiophene at the arylthiophene bridge or to the pyrrole heterocycle, which plays the role of donor group. Compound 2 showed a different reactivity behavior in the presence of the Vilsmeier reagent or with tetracyanoethylene (TCNE) giving compounds 4a and 4b functionalized, respectively, at the 2 or on the 3-position of the pyrrole heterocycle. Their optical (linear and first hyperpolarizability), electrochemical, and thermal properties have been examined. Hyper-Rayleigh scattering (HRS) in dioxane solutions using a fundamental wavelength of 1064nm was employed to evaluate their second-order nonlinear optical properties. Of these systems, thiobarbituric acid derivative 5b functionalized in the thiophene ring exhibits the largest first hyperpolarizability (β=2480×10−30esu, T convention) compared to the corresponding compound 4c substituted on the pyrrole heterocycle (β=290×10−30esu, T convention). Good to excellent thermal stabilities were also obtained for push–pull compounds 4 and 5 (270–288°C). This multidisciplinary study shows that modulation of the optical and electronic properties can be achieved by introduction of the acceptor groups in the thiophene of the arylthiophene bridge. The measured molecular first hyperpolarizabilities and the observed electrochemical behavior are quite sensitive to the position of acceptor group on the heterocyclic system (on the thiophene or on the pyrrole ring) as well as the strength of the acceptor moieties. Moreover, the combination of their good nonlinearity and high thermal stability make them good candidates for second-order nonlinear optical applications.

Synthesis of dithienopyrrole derivatives

Reactions of N-substituted succinimides with the Vilsmeier reagent leading to isomeric diformyldichloropyrroles were studied. The latter compounds were used for the synthesis of N-substituted dithieno[2,3-b:2′,3′-d]pyrrole and dithieno[2,3-b:3′,2′-d]pyrrole and their bromo derivatives as well. Dimers of N-alkyldithieno[2,3-b:2′,3′-d]pyrrole, novel promising materials for organic semiconductors, were synthesized.

ChemInform Abstract: An Approach to Synthesis of (Z)‐2‐Chloro‐1,3‐diarylpropen‐1‐ones by Vilsmeier Reagent (Bis‐(trichloromethyl) carbonate/DMF).

AbstractTreatment of epoxides (I) with Vilsmeier reagent generated from triphosgene and DMF results in the selective formation of (Z)‐2‐chloro‐propenones (II) (14 examples).

ChemInform Abstract: New Preparation Method for Vilsmeier Reagent and Related Imidoyl Chlorides.

AbstractA novel method for the synthesis of Vilsmeier reagent (II) and related imidoyl chlorides uses OPC as chlorinating agent.

ChemInform Abstract: Novel Method for the Synthesis of 4‐Formyl‐1,3‐dimethylpyrazole

Abstractvia reaction of acetone methylhydrazone (I) with Vilsmeier reagent

ChemInform Abstract: Efficient Synthesis of Methyl 4‐Chloro‐6‐fluoro‐3‐formyl‐2H‐chromene‐2‐carboxylate and Its Derivatives.

AbstractTitle compound (III), conveniently synthesized from chromanone derivative (I) using Vilsmeier reagent, undergoes condensation and cyclization reactions with active methylene compounds.

ChemInform Abstract: A New Synthesis of Alkyl (E)‐(3‐Dimethylamino)acrylates.

AbstractThe stereoselective synthesis of title compounds (III) and (VI) is achieved by reaction of Vilsmeier reagent, in situ generated from DMF and SOCl2, with ketene acetals.

Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors

Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2-substituted spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50-75 g scale with minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors.

Synthesis of 2-amino-imidazoles, purines, and benzoxazolamines through DIB oxidation

A wide range of fused 2-amino-imidazoles and 2-amino-benzoxazoles can be prepared in one-pot under very mild conditions from 1,2-diamino-arenes or 2-amino-phenols and Vilsmeier reagents. The oxidation proceeds using diacetoxy-iodobenzene (DIB) and is tolerant to different functionalities.

Application of Vilsmeier Reagents in Cyclization in Recent Years

Application of Vilsmeier Reagents in Cyclization in Recent Years

New preparation method for Vilsmeier reagent and related imidoyl chlorides

An environmentally benign and inexpensive preparation method is described of some imidoyl chlorides, including the Vilsmeier reagent (VR), by using phthaloyl dichloride. Synthetic applications were demonstrated using the isolated VR or VR prepared in situ for the transformation of acids to acid chlorides, alcohols to chlorides, and the formylation of dimethylaminobenzene.

Development of Two Scalable Syntheses of 4-Amino-5-aminomethyl-2-methylpyrimidine: Key Intermediate for Vitamin B1

Two scalable processes for the synthesis of 4-amino-5-aminomethyl-2-methylpyrimidine (2) are described. In the first approach, the less expensive 2-cyanoacetamide was reacted with Vilsmeier reagent to afford enamine 18, followed by the condensation with acetamidine to produce the 4-amino-2-methylpyrimidine-5-carbonitrile (6); subsequent hydrogenation gave 2 in 65% overall yield. In the second approach, malononitrile was treated with the ionic salt 21, prepared in situ from DMF and dimethyl sulfate, to give 18, which, without isolation was reacted with acetamidine hydrochloride to afford the common intermediate 6. Overall yield of this approach was 70%. Both methods are performed in a convenient manner suitable for industrial use.

ChemInform Abstract: 3‐Thiolated 2‐Azetidinones: Synthesis and in vitro Antibacterial and Antifungal Activities.

AbstractA series of azetidinones of type (III) (27 examples) is prepared by the Staudinger cycloaddition reaction of Schiff bases with S‐substituted mercaptoacetic acids in the presence of the Vilsmeier reagent.

An approach to synthesis of (Z)-2-chloro-1,3-diarylpropen-1-ones by Vilsmeier reagent (bis-(trichloromethyl) carbonate/DMF)

Abstract A series of ( Z )-2-chloro-1,3-diarylpropen-l-ones were unexpectedly synthesized in moderate yields by treatment of easily available 2,3-epoxy-l, 3-diarylpropan-1-ones with Vilsmeier reagent, which was derived from bis(trichloromethyl) carbonate (BTC, triphosgene) and DMF. A possible mechanism was also proposed, where sequential ring-opening, halogenation and elimination reactions were involved.

Synthesis of Substituted 3-Cyano- and 3-(Arenesulfonyl)indoles from o-Nitrobenzyl Cyanides and Sulfones

Formation of enamines, in the reaction of o-nitrophenyl­acetonitriles with Vilsmeier reagents, followed by reductive cyclization using Zn in acetic acid, leads to variously substituted 3-cyanoindoles, possessing aryl, alkyl, and aminoalkyl substituents at C-2. The method, when starting from the appropriate o-nitrobenzylsulfones, allows the synthesis of substituted 3-(arenesulfonyl)-­indoles.

ChemInform Abstract: Ring and Side‐Chain Formylated Pyrazoles from Acetophenone Azines and Vilsmeier′s Reagent.

AbstractThe effect of the product formation by using excess of the Vilsmeier reagent is presented.