Vilsmeier-Haack reagent : A facile synthesis of 2-( 4-chloro-3 , 3-dimethyl-7-phenoxyindolin-2-ylidene ) malonaldehyde and transformation into different heterocyclic compounds

Article history: Received March 20, 2013 Received in Revised form July 7, 2013 Accepted 28 July 2013 Available online 30 July 2013 2-(5-Chloro-2-phenoxyphenyl)hydrazine was converted to corresponding 3H-indole by Fischer method utilizing the isopropyl methyl ketone in acetic acid. The reaction of 3H-indole with Vilsmeier-Haack reagent furnished aminomethylene malonaldehyde in excellent yield while the reactions of malonaldehyde with hydrazine, arylhydrazines, amines, cyanoacetamide and hydroxylamine hydrochloride, led to the corresponding pyrazole derivatives, enamines, cyanopyridone, and cyanoacetamide derivatives respectively. © 2013 Growing Science Ltd. All rights reserved.


Introduction
Chloromethyleneiminium salts, commonly known as highly versatile Vilsmeier-Haack reagent, 1 usually generated in situ by the treatment of POCl 3 with an N,N-disubstituted formamides (e.g., DMF), is very useful in the synthetic transformations.Selected applications of this reagent include: formylation, 2,3 cyclohaloaddition, 4 cyclization 5 and ring annulations. 6A wide variety of alkene derivatives, 7 carbonyl compounds, 8 activated methyl and methylene groups bearing chemicals, 9 and oxygen 10 as well as nitrogen nucleophiles 11 undergo the reactions with Vilsmeier reagent to yield the corresponding iminium salts.
In 1959, Fritz 12 reported the N-formylation of a 3,3-disubstituted 3H-indole (indolenine) 1 leading to 2 by utilization of Vilsmeier reagent formed from DMF and POCl 3 .Further reaction of 2 with the Vilsmeier reagent, followed by hydrolysis produced compound 4. Formation of this product probably involves the intermediate 3, from which the N-formyl group is hydrolytically removed during workup (Scheme 1).

Scheme 1
Recently, we demonstrated [13][14][15] that the 2-CH 3 formylation reaction of some of 2,3,3trimethylindolenines (3H-indoles) by Vilsmeier reagent furnished aminomethylene malonaldehydes.Thus formed 1,3-dialdehyde compounds undergo reaction with various nucleophiles to yield a wide range of new heterocyclic compounds.As an extension of our previous studies, herein we demonstrated the formylation of another indolenine to produce corresponding malonaldehyde as well as synthesis of various heterocyclic compounds by condensations of malonaldehyde with various arylhydrazines and cyanoacetamide leading to both 5-and 6-membered heterocycles, respectively.

Scheme 2
Reaction of 7 with isopropyl methyl ketone in a Fischer reaction condition furnished the 3Hindole 8 in a good yield (Scheme 3).

Scheme 3
The structure of 3H-indole 8 was confirmed on the basis of analysis of 1 H-NMR spectrum possessing six-hydrogen singlets for the geminal methyl groups, at δ 1.55 ppm and three-hydrogen singlet signals for the imine-methyl group, at δ 2.29 ppm.
The reaction of 8 with Vilsmeier reagent at 75 °C, led to diformylation of imine-methyl group in excellent yield (Scheme 4).The structure of malonaldehyde 9 was confirmed by its spectral data.The IR absorptions at 3159 and 1675 ,1639 cm -1 support a presence of N-H and two carbonyl groups, thus in 1 H-NMR spectrum signal for the N-hydrogen appearing at δ 13.55 ppm and two aldehyde hydrogens at δ 9.75 ppm.The 13 C-NMR spectrum of 9 showed the presence of two carbon signals at 187.66 and 192.64 ppm corresponding to CHO groups.

Scheme 4
1,3-Dicarbonyl compounds can be used as important building blocks in the syntheses of various heterocycles 16 , which often show high biological activities 16,17 .The reaction of the substrate 9 with hydrazine hydrate and substituted arylhydrazines at room temperature and reflux conditions, respectively, afforded desired products 10a-d in quantitative yields (Scheme 5).

Scheme 5
As extension of this work, we also examined the reactions of hydroxylamine hydrochloride, cyanoacetamide and arylamines with aminomethylene malonaldehyde 9.
The corresponding cyanoacetamide derivative 11 was readily achieved by refluxing a mixture of malonaldehyde 9 and hydroxylamine hydrochloride in ethanol (Scheme 6).

Scheme 6
The X-ray diffraction data for similar compound 18 showed that the orientation of the acetamide group arises from intramolecular hydrogen bonding between the indole N-H and the carbonyl group (Scheme 7).

N H 3 C CH 3 CN CH 3
Cl O NH 2

Scheme 7
The compound 9 was allowed to react with cyanoacetamide under reflux condition in ethanol to obtain cyanopyridone derivative 12.The structure of compound 12 was elucidated from its spectral data.The 1 H-NMR spectrum showed two singlet at δ 8.42 and 8.66 ppm respectively, belonged to two protons of pyridone.The broad singlet appearing around δ 13.07 ppm confirmed the presence of pyridone N-H bond (Scheme 8).

Scheme 8
Finally, attempt to synthesis quinoline derivatives starting from arylamines and malonaldehyde 9 was unsuccessful but this condensation gave enamines 13a-d in high yields (Scheme 9).

Scheme 9
A study of the 1 H-NMR spectrum of enamine 13b showed that both E and Z isomers of 13b have been formed in a ratio 1:1.Thus, there were two singlets at δ 8.39 and δ 8.43 ppm in a ratio 1:1, corresponding to CH=N and a pair of siglets at δ 14.08 and δ 14.12 ppm, again in a ratio of 1:1 assigned to NH protons (Scheme 10).Scheme 10

Conclusion
In summary, we have examined the reaction of 3H-indole with Vilsmeier-Haack reagent.This study revealed that the formed malonaldehyde from formylation reaction could be cyclized using various arylhydrazines and cyanoacetamide to afford substituted pyrazoles and cyanopyridone.Also, reaction of malonaldehyde with hydroxylamine and primary aromatic amines furnished cyanoacetamide and enamine derivatives, respectively.respectively.Chemical shifts δ are in parts per million (ppm) measured in CDCl 3 and DMSO-d 6 as solvents and related to TMS as the internal standard.IR spectra were recorded on a Thermonicolet-Nexus 670 FT-IR instrument.Elemental analyses were performed on Heraeus CHN-O rapid analyzer.

General procedure for synthesis of (10b-d).
A mixture of the malonaldehyde 9 (0.1 g, 0.29 mmol) and aryl hydrazinium chloride (0.29 mmol), in absolute ethanol (15 mL) was heated at reflux and stirred for 2-5 h.After cooling and concentrating the resulting crystals were collected by filtration and recrystallized from ethanol to give the corresponding pyrazoles.