Vilsmeier Formylation Research Articles

Concise Syntheses of the Cruciferous Phytoalexins Brassilexin (IIIa), Sinalexin (Vb), Wasalexins (X), and Analogues: Expanding the Scope of the Vilsmeier Formylation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of 3-Substituted Arylpyrazole-4-carboxylic Acids

A method was suggested for preparing previously unknown 3-aryl-substituted pyrazole-4-carboxylic acids, involving Vilsmeier formylation of semicarbazones of 26 available mono- and disubstituted acetophenones and 2-acetylthiophene followed by oxidation of the resulting 3-aryl-substituted pyrazole-4-carboxaldehydes under the action of potassium permanganate. The mechanism of the formylation reaction is discussed. The method successfully works even with acetophenones containing alkyl substituents. In the latter case, an additional stage that involves isolation of pyrazole-4-carboxylic acids as their silyl esters is used.

Syntheses Based on 4-Chloro-1-[3,5-di(trifluoromethyl)phenyl]-, 4-Chloro-1-(2,4-difluorophenyl)-5-formyl-3-methyl-6,7-dihydroindazoles, and 4-Chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazoles

Vilsmeier formylation of 1-[3,5-di(trifluoromethyl)phenyl]- and 1-(2,4-difluorophenyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazoles gave the corresponding 1-aryl-4-chloro-5-formyl-3-methyl-6,7-dihydroindazoles. Reaction of the latter with amidines, o-phenylenediamine, hydrazine, or hydroxylamine gave a series of 1-aryl-3-methyl-6,6-dihydroindazoles annelated at positions 4 and 5. The reaction of 4-chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazole with substituted anilines gave 5-arylaminomethylene-4-oxo- or 5-arylaminomethylene-4-arylimino-3-methyl-1-(2-pyridyl)-4,5,6,7-tetrahydroindazoles depending on the molar ratio of reagents and the nucleophilicity of the amines.

Formation of 6,10‐Diphenyl‐Substituted Heptalene‐4,5‐dicarboxylates

AbstractIt is shown that 4,8‐diphenylazulene (1) can be easily prepared from azulene by two consecutive phenylation reactions with PhLi, followed by dehydrogenation with chloranil. Similarly, a Me group can subsequently be introduced with MeLi at C(6) of 1 (Scheme 2). This methylation led not only to the expected main product, azulene 2, but also to small amounts of product 3, the structure of which has been determined by X‐ray crystal‐structure analysis (cf. Fig. 1). As expected, the latter product reacts with chloranil at 40° in Et2O to give 2 in quantitative yields. Vilsmeier formylation of 1 and 2 led to the formation of the corresponding azulene‐1‐carbaldehydes 4 and 5. Reduction of 4 and 5 with NaBH4/BF3 ⋅ OEt2 in diglyme/Et2O 1 : 1 and BF3 ⋅ OEt2, gave the 1‐methylazulenes 6 and 7, respectively. In the same way was azulene 9 available from 6 via Vilsmeier formylation, followed by reduction of azulene‐1‐carbaldehyde 8 (Scheme 3). The thermal reactions of azulenes 1, 6, and 7 with excess dimethyl acetylenedicarboxylate (ADM) in MeCN at 100° during 72 h afforded the corresponding heptalene‐4,5‐dicarboxylates 11, 12, and 13, respectively (Scheme 4). On the other hand, the highly substituted azulene 9 gave hardly any heptalene‐4,5‐dicarboxylate.

Vilsmeier Formylation of Hydrazones and Semicarbazones Derived from Alkyl, Benzyl, and Cycloalkyl Methyl Ketones

Formylation of ten accessible phenylhydrazones and semicarbazones derived from alkyl, benzyl, and cycloalkyl methyl ketones with the complex of POCl3 with dimethylformamide was studied. Depending on the electronic and steric structure of the substrates, the reaction yields 1-phenyl- or 1-unsubstituted 3,4-dialkyl-, 3-alkyl-4-aryl-, or 3-alkyl-4-formylpyrazoles. These compounds can be readily oxidized into the corresponding carboxylic acids.

Concise Syntheses of the Cruciferous Phytoalexins Brassilexin, Sinalexin, Wasalexins, and Analogues: Expanding the Scope of the Vilsmeier Formylation

Efficient syntheses of the phytoalexins brassilexin, sinalexin, and analogues are demonstrated through the application of the Vilsmeier formylation to indoline-2-thiones followed by a new aqueous ammonia workup procedure. Similarly, a very concise two-pot synthesis of the phytoalexins wasalexins using sequential formylation-amination of indolin-2-ones is described. Remarkably, this novel aqueous ammonia workup allows the sequential one-pot formylation-amination, expanding substantially the scope of the Vilsmeier formylation of both indoline-2-thiones and indolin-2-ones. The examination of the formylation-amination reaction and optimization of conditions, as well as the syntheses and antifungal activities of several brassilexin analogues, are reported.

The Dithianyl Group as a Synthon in Porphyrin Chemistry: Condensation Reactions and Preparation of Formylporphyrins under Basic Conditions.

Vilsmeier formylation is one of the most widely used substitution reactions for the functionalization of porphyrins. However, its utility is limited by the electrophilic/acidic reaction conditions, deactivation of the aromatic system and regiochemical problems, the requirement for metal complexes and necessity for subsequent demetalation under harsh conditions, and low functional group tolerance. To overcome these limitations, the dithianyl group has been utilized as a latent formyl synthon in porphyrin chemistry. 2-Formyl-1,3-dithiane can be used directly in pyrrole condensation reactions to regioselectively yield porphyrins with up to four dithianyl residues. Likewise, 5-dithianyldipyrromethane could be prepared quantitatively as a key building block for various porphyrin condensation reactions yielding the respective free base formylporphyrins after deprotection. Additionally, dithianyllithium can be used as a reagent for the direct aromatic substitution of metallo- and free base porphyrins under nucleophilic conditions.

The Dithianyl Group as a Synthon in Porphyrin Chemistry: Condensation Reactions and Preparation of Formylporphyrins under Basic Conditions

Vilsmeier formylation is one of the most widely used substitution reactions for the functionalization of porphyrins. However, its utility is limited by the electrophilic/acidic reaction conditions, deactivation of the aromatic system and regiochemical problems, the requirement for metal complexes and necessity for subsequent demetalation under harsh conditions, and low functional group tolerance. To overcome these limitations, the dithianyl group has been utilized as a latent formyl synthon in porphyrin chemistry. 2-Formyl-1,3-dithiane can be used directly in pyrrole condensation reactions to regioselectively yield porphyrins with up to four dithianyl residues. Likewise, 5-dithianyldipyrromethane could be prepared quantitatively as a key building block for various porphyrin condensation reactions yielding the respective free base formylporphyrins after deprotection. Additionally, dithianyllithium can be used as a reagent for the direct aromatic substitution of metallo- and free base porphyrins under nucleophilic conditions.

A new route to meso-formyl porphyrins.

Prior syntheses of porphyrins bearing meso-formyl groups have generally employed the Vilsmeier formylation of an acid-resistant copper or nickel porphyrin. A new approach for the synthesis of free base porphyrins bearing one or two (cis or trans) meso-formyl substituents entails the use of a dipyrromethane bearing an acetal group at the 5-position, a dipyrromethane-1-carbinol bearing an acetal group at the 5-position or carbinol position, or a dipyrromethane-1,9-dicarbinol bearing an acetal group at a carbinol position. Treatment of the resulting meso-acetal-substituted free base porphyrin to gentle acidic hydrolysis yields the corresponding meso-formyl porphyrin.

Formylation of 6-Aminouracil with Vilsmeier Reagent

Oxopyrimidine-5-carbaldehydes I and some of their derivatives (azomethines, hydrazones) show promise as synthetic precursors of antitumor agents [1, 2]. Aldehydes I are usually synthesized by the Reimer Tiemann reaction [3], controlled oxidation of 5-hydroxymethylpyrimidines [4], or Vilsmeier reaction. The latter reaction can be accompanied by exchange chlorination of oxo groups of the pyrimidine ring. For example, heating of 6-aminouracil II with POCl3 in DMF yields 6-amino-2,4-dichloro-5-formylpyrimidine [5]. At the same time, there are indications in the literature [6] that Vilsmeier formylation of amine II can be performed so as to leave the oxo groups intact.

Formylation, Dicyanovinylation and Tricyanovinylation of 5‐Alkoxy‐ and 5‐Amino‐Substituted 2,2′‐Bithiophenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Formylation, dicyanovinylation and tricyanovinylation of 5-alkoxy- and 5-amino- substituted 2,2′-bithiophenes

Several donor–acceptor-substituted bithiophenes were synthesized by functionalization of the corresponding 5-alkoxy- or 5-aminobithiophenes 1 by different methods: Vilsmeier formylation, metalation followed by reaction with DMF, direct tricyanovinylation reaction using TCNE or Knoevenagel condensation starting from the corresponding 5-formyl- derivatives of 1 .

DOTTADs--readily made novel metal ligands with multivariant functionality--trans-DOTTADs and semi-DOTTADs.

Two new ligand systems related to the previously described DOTTADs have been generated in a simple one step reaction. The first, trans-DOTTADs, were formed by Vilsmeier formylation (followed by cyclisation and N-demethylation) of 2,6-dimethyl-3,5-pyrazine-dicarboxylic acid, to give the novel bis-pyridinopyrazine dialdehyde ligands. The corresponding pyrazine diester, reacted similarly to an intermediate iminium ion stage, which gave trans-DOTTAD imines on work-up with amines. The treatment of Hantzsch ester with two equivalents of benzaldehyde gave 7-phenyl-2-(2-phenylethenyl)-7,8-dihydropyrano[4,3-b]pyridin-5-one-3-carboxylic acid. This product underwent similar cyclisation with Vilsmeier reagents to give, for example, 6-methyl-2-(2-phenylethenyl)-8-(phenylhydroxymethyl)-6H-[1,6]naphthyridin-5-one-3-carboxylic acid, an example of a semi-DOTTAD.

A Very Simple Route to Benzonaphtho[1,5]diazocines Using Vilsmeier Reagents via the “t‐Amino‐Effect”.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Scale-Up of a Vilsmeier Formylation Reaction: Use of HEL Auto-MATE and Simulation Techniques for Rapid and Safe Transfer to Pilot Plant from Laboratory

The application of reaction calorimetry and process modelling to allow for the rapid and safe scale-up of a Vilsmeier formylation reaction to the pilot plant will be described. This transformation was a key step in the preparation of the backbone amide linker (the so-called “BAL” handle) for solid-phase chemistry. In particular, use was made of Auto-MATE equipment from Hazard Evaluation Laboratories (HEL) and “Reaction Simulator” software to derive a thermokinetic model which allowed us to simulate heat-flow data on-scale. The model was then refined using a HEL SIMULAR 1-L calorimeter, and a direct comparison of the data showed there to be a 20% error in the enthalpy data gathered from the smaller Auto-MATE. The use of a preformed Vilsmeier reagent and dichloromethane as a reaction solvent gave a “square-wave” profile typical of a feed-controlled reaction. These conditions were successfully scaled to a 50-L pilot-plant vessel.

Asymmetric synthesis of a selective endothelin A receptor antagonist

An asymmetric synthesis of a selective endothelin A receptor antagonist 1b is described. A highly substituted pyridine intermediate 11a was efficiently prepared via a mono-amination of inexpensive 2,6-dichloropyridine followed by a Vilsmeier formylation. Asymmetric conjugate addition of aryl lithium 14 to the chiral oxazoline 13 followed by hydrolysis afforded 15 in 90% ee. Pd(OAc) 2/dppf catalyzed carbonylation followed by chemoselective addition of aryl lithium 18 gave ketone 19 . Diastereoselective reduction of the ketone with LS-Selectride ® followed by concomitant activation of the resulting alcohol and cyclization gave the late intermediate 21 . Deprotection and purification by crystallization furnished the enantiomerically pure target molecule 1b in 10% overall yield from 11a .

A new fluorous/organic amphiphilic ether solvent, F-626: execution of fluorous and high temperature classical reactions with convenient biphase workup to separate product from high boiling solvent

A new fluorous/organic amphiphilic ether solvent, 1 H,1 H,2 H,2 H-perfluorooctyl 1,3-dimethylbutyl ether (F-626), is introduced. The basic properties of F-626, especially the partition coefficients with organic solvents/FC-72 (perfluorohexane), were investigated. F-626 was easy to remove by fluorous biphase treatment. Using F-626 as a solvent, LAH reduction, catalytic hydrogenation, and fluorous reductive radical reactions were successful. Classical high temperature reactions up to 200°C, such as the Vilsmeier formylation, the Wolff–Kishner reduction, and the Diels–Alder reaction, were also examined in F-626. The yields of the products in F-626 were almost comparable with those conducted in common organic solvents, which prove that F-626 has the potential to be an easily recyclable high boiling solvent.

A Very Simple Route to Benzonaphtho[1,5]Diazocines Using Vilsmeier Reagents via the ‘t-Amino Effect’

The novel fused heterocyclic systems 7,8,13,14-tetrahydrobenzo[b]naphtho[1,2-f][1,5]diazocine and 7,8,13,14-tetrahydrobenzo[b]naphtho[2,1-f][1,5]diazocine were prepared in moderate yields in a one step reaction by Vilsmeier formylation of 1-dimethyl-aminonaphthalene or 2-dimethylaminonaphthalene, respectively, by way of the ‘t-amino effect’. Novel rearranged by-products were formed from 2-dimethylaminonaphthalene.

Vilsmeier formylation of 2-carboxyindoles and preparation of O-benzylhydroxyureas on solid phase.

The Vilsmeier formylation has been introduced for the solid-phase functionalization of five different 2-carboxyindoles. The aldehyde functionality has been utilized in the preparation of O-benzylhydroxyureas.

Investigations on the directive effects of a single meso-substituent via nitration of 5,12,13,17,18-pentasubstituted porphyrins: syntheses of conjugated β-nitroporphyrins

Vilsmeier formylation of 5-substituted 1,9-diunsubstituted dipyrromethanes afforded 1,9-diformyldipyrromethanes in good yields. Their MacDonald condensation with tetra-β-alkyldipyrromethanes produced 5,12,13,17,18-pentasubstituted porphyrins. A meso-electron-donating group, presumably acting by destabilizing the porphyrin a 2u ground state, directs the nitrations to the meso-carbons. β-Nitration takes place on porphyrins bearing a meso-electron-withdrawing group. Unhindered β-nitro groups are shown to exert stronger electronic effects relative to meso-nitro groups by conjugating effectively with the porphyrin macrocycle.