INTRODUCTION

2,6-Difluoroanilineis useful as an intermediate in the manufacture of a variety of chemical products like dyes, pharmaceuticals and agricultural chemicals. presently manufactured involving the following reaction sequence:

(i) Ammoxidation (ii) Halogen exchange (iii) Hydration (iv) Hoffman rearrangement

In addition, 2, 6-Dichlorotoluene itself is not readily available. Thus as a result of the complexities of the chemistry, although commercially available, 2, 6-Difluoroaniline is quite expensive.

Alternative technologies have been suggested to manufacture 2, 6-Difluoroaniline, but they also have serious drawbacks. For example, fluorinated aromatics are often prepared by diazonium chemistry in which an amino moiety transformed into a fluorine substituent by reaction with nitrous acid to from a diazonium salt and subsequent decomposition of the diazonium salt in the presence of fluoride. However, diazonium salts are unstable and the decomposition reaction is highly exothermic. In addition, the decompositions are generally conducted in highly reactive corrosive anhydrous hydrofluoric acid.

Alternatively, 2, 6-difluoroaniline has also been prepared via lithiation of 1, 3-difluorobenzene followed by carbonation to the carboxylic acid and conversion of the acid moiety to the amine with hydrazoic acid. (See British Patent 1,080,167). Unfortunately, neither lithiation nor hydrazoic acid lend themselves to large scale use.

More recently, 2, 6-difluoroaniline has been prepared from 1-chloro-3, 5-difluorobenzene by the following reaction scheme.

(i) Chlorination (ii) Nitration (iii) Reduction

Unfortunately, 3, 5-difluorochlorobenzene is not commercially available on a large scale; nor is the 1, 3, 5-trichlorobenzene from which it can most conveniently be prepared.

The other alternative route is reported

(i) Chlorination (ii) Reduction

Though it is two steps synthesis the isolation of desired product by distillation is so difficult and very poor yield.

The present invention concerns a process for the preparing 2, 6-difluoroalinie from the 1, 2, 4-trichlorobenzene by the following reaction scheme, which is novel with good yield and commercially available starting material.

(i) Chlorination (ii) Nitration (iii) Halogen exchange (Halex reaction) (iv) Reduction and des-chlorination

EXPERIMENTAL:

Thin layer chromatography was run on silica gel-G and visualization was done using UV light or iodine. IR spectra were recorded by Perkin-Elmer 1000 instrument in KBr pellets. ¹H-NMR spectra were recorded in CDCl₃or DMSO-D6 solvent using trimethyl silane as the internal standard by the 300MHz spectrometer. By Jeol-JMS D-300 spectrometer, mass spectra were recorded. Starting materials which were used in this chapter were obtained from commercial sources and used as such.

RESULTS AND DISCUSSION:

1, 2, 4-Trichlorobenzene (1) reacts with chlorine gas using EDC as solvent AlCl₃as catalyst at 50^oC about 12hr to offered 1, 2, 4, 5-Tetrachlorobenzene (2) which on further reaction with Fuming nitric acid and concentrated sulfuric acid gave 2,3, 5,6-Tetrachloronitrobenzene (3), this obtained compound 3 reaction with Potassium fluoride in DMF solvent at reflux condition to offered 3,5-Dichloro-2,6-difluoronitrobenzene (4) which on further reaction with Raney-Ni under Hydrogen atmosphere using methanol as solvent gave title compound (5). All these compounds were characterized by spectral analysis.

SCHEME:

(i) Cl2/EDC/AlCl3 (ii) Fuming HNO3/Conc. H2SO4

(iii) KF/DMF/TBAB (iv) Raney-Ni/H2/MeOH

1, 2, 4, 5-Tetrachlorobenzene (2):

To a solution of AlCl3 (2% w/w) in Ethylene dichloride (3 volume), 1, 2, 4-Trichlorobenzene (1) (0.02mol) was added. The reaction mixture was stirred under chlorine gas atmosphere at 50^oC about 14hr then poured into a beaker contain an ice water mixture and layer separated, organic layer was distilled to obtained solid, this solid have the mixture of isomers70:30 (desired : undesired) by hexane recrystallization we have isolated the single and desired isomer of product.

¹H NMR (DMSO-d6, 300MHz): = 7.49 (s, 2H),MS: m/z, 216 (M+2)

2, 3, 5, 6-Tetrachloronitrobenzene (3):

To a solution of 1, 2, 4, 5-Tetrachlorobenzene (2) (0.02mol) and Conc. Sulfuric acid (98%, 2 volume), Fuming Nitric acid (0.025mol) was added drop wise at 5^oC, then the reaction mixture stirred at room temperature overnight water was added and the precipitated obtained was filtered off dried.

¹H NMR (DMSO-d6, 300MHz): = 7.88 (s, 1H),

MS: m/z, 262(M+2)

3, 5-Dichloro-2, 6-difluoronitrobenzene (4):

To a solution of 2, 3, 5, 6-Tetrachloronitrobenzene (3) (0.02mol) in DMF, Potassium fluoride (0.03mol) followed by Tetrabutylammonium bromide (0.001mol) were added refluxed about 14hr separated the byproduct potassium chloride by filtration, filtrate was concentrated, pure material obtained by high vacuum distillation.

¹H NMR (DMSO-d6, 300MHz): = 7.96 (t, 1H),

MS: m/z, 229 (M+2)

2, 6-Difluoroaniline (5):

In a Parr Hydrogenator to a solution of 3, 5-Dichloro-2, 6-difluoronitrobenzene (4) (0.02mol) in methanol, Raney-Ni was added under nitrogen atmosphere and passed hydrogen gas around 20kg heated the reaction at 120^oC about 25-30hr this duration in reaction, reduction of nitro to amine and des-chlorination both conversions takes place, after completion of reaction filtered the Raney-Ni concentrated the methanol and pure title product was collected by high vacuum distillation.

¹H NMR (DMSO-d6, 300MHz): = 6.74 (m, 3H), 5.32 (brs, 2H, NH₂), MS: m/z, 130(M+1).

REFERENCES:

1. Nippon Kagaku Kaishi, (12), 2006-11; 198.

2. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 20B (12), 1086-7; 1981.

3. Faming Zhuanli Shenging, 1005622333, 01 Jun 2016.

4. U.S., 5041674, 20 Aug 1991.

Received on 13.03.2023 Modified on 18.04.2023

Asian J. Research Chem. 2023; 16(3):235-236.

DOI: 10.52711/0974-4150.2023.00038