Synthesis and Application of 2,3-Difluorobromobenzene

₆H₃BrF₂, and the CAS is 38573-88-5. 2,3-Difluorobromobenzene is a colorless to pale yellow liquid with a boiling point of 234 °C. At 25°C, its density is 1.724 g/mL. 

Synthetic routes

Fig. 2 The synthetic method 1 of 1-Bromo-2,3-difluorobenzene.

Add 50% aqueous solution of KOH (18.0 g, 160 mmol) to a mixture of 1-bromo-5,5,6,6-tetrafluorocyclohex-1-ene (11.65 g) and triethylbenzylammonium chloride (0.15 g, 0.7 mmol) at 30-35°C for 30 minutes. Keep the reaction mixture at 75-85°C for 2 hours. Cool the reaction mixture. Dilute the reaction mixture with water. Extract the organic product with CH₂Cl₂. Dry the organic product over CaCl₂. Distill the organic product. ¹H NMR (CDCl₃, 300.1 MHz), δ: 7.00-7.16 (m, 1H, Ar); 7.17-7.29 (m, 1H, Ar); 7.34-7.47 (m, 1H, Ar). ¹³C NMR (CDCl₃, 75.5 MHz), δ: 110.40 (d, C(1), J = 17.5 Hz); 116.40 (d, C(4), J = 17.7 Hz); 124.70 (dd, C(5), J = 7.1 Hz, J = 5.0 Hz); 128.23 (d, C(6), J = 3.6 Hz); 148.10 (dd, C(2), J = 248.8 Hz, J = 14.3 Hz); 150.92 (dd, C(3), J = 251.9 Hz, J = 13.3 Hz). ¹⁹F NMR (CDCl₃, 282.4 MHz), δ: -130.9 (m, 1 F, Ar), -134.8 (m, 1 F, Ar). BP 157-158°C. Elemental Analysis Found (%): C, 37.54; H, 1.50. C₆H₃BrF₂. Calculated (%): C, 37.34; H, 1.52. Mass Spec MS, m/z (Irel (%)): 194, 192 [M]⁺ (100, 99), 113 [M-Br]⁺ (88), 63 (60) [1].

Fig. 3 The synthetic method 2 of 1-Bromo-2,3-difluorobenzene.

Add a 50% aqueous solution of KOH (140.0 g, 1.25 mol) to a mixture of 3,4-dibromo-1,1,2,2-tetrafluorocyclohexane (100.0 g) and triethylbenzylammonium chloride (0.94 g, 4 mmol) maintaining temperature in a range of 20-30°C for 1.5 hours. Stir the reaction mixture at 80-85°C for 2 hours. Distill off the organic product with water vapor. Dry the organic product over CaCl₂. Distill the organic product. ¹H NMR (CDCl₃, 300.1 MHz), δ: 7.00-7.16 (m, 1H, Ar); 7.17-7.29 (m, 1H, Ar); 7.34-7.47 (m, 1H, Ar). ¹³C NMR (CDCl₃, 75.5 MHz), δ: 110.40 (d, C(1), J = 17.5 Hz); 116.40 (d, C(4), J = 17.7 Hz); 124.70 (dd, C(5), J = 7.1 Hz, J = 5.0 Hz); 128.23 (d, C(6), J = 3.6 Hz); 148.10 (dd, C(2), J = 248.8 Hz, J = 14.3 Hz); 150.92 (dd, C(3), J = 251.9 Hz, J = 13.3 Hz). ¹⁹F NMR (CDCl₃, 282.4 MHz), δ: -130.9 (m, 1 F, Ar), -134.8 (m, 1 F, Ar). Mass Spec MS, m/z (Irel (%)): 194, 192 [M]⁺ (100, 99), 113 [M-Br]⁺ (88), 63 (60) [1].

Fig. 4 The synthetic method 3 of 1-Bromo-2,3-difluorobenzene.

A-bromosuccinimide (78.30 g, 0.440 mol) was added to a stirred suspension of compound 5 (35.00 g, 0.222 mol) in acetonitrile (300 ml) under dry nitrogen. The stirred mixture was heated under reflux for 16 h (GLC and TLC analysis revealed a complete reaction) and poured into water. The product was extracted into hexane (×2), and the com bined organic extracts were washed successively with sodium bisulphite and sodium bicarbonate and dried (MgSO₄). The solvent was distilled off at atmosphere pressure (68°C) and the product was distilled at atmospheric pressure. Yield 30.0 g (70%). bp 158°C. ¹H NMR (400 MHz, CDCl₃), δ 6.98(1H, dddd), 7.11(1H, dddd), 7.29(1H, dddd). MS m/z 194(M⁺), 192(M⁺) [2].

Application

New metabolites from the microbial oxidation of fluorinated aromatic compounds

m-Bromo-alpha,alpha,alpha-trifluorotoluene (1) and 1-bromo-2,3-difluorobenzene (4) were subjected to microbial oxidation by Pseudomonas putida strain 39/D and the corresponding Escherichia coli recombinant microorganism (Strain JM109(pDTG601)), which express toluene dioxygenase. The absolute stereochemistry of the major oxidation products have been determined as cis-(2R,3S)-5-bromo-2,3-dihydroxy-alpha,alpha,alpha-trifluoromethylcyclohexa-4,6-diene (2), and cis-(2S,3S)-1-bromo-5,6-difluoro-2,3-dihydroxy-4,6-diene (5). The regiochemistry of a minor metabolite has been established as cis-5-bromo-3,4-dihydroxy-alpha,alpha,alpha-trifluoromethylcyclohexa-1,5-diene (3) [3].

Regioselective synthesis of 2,3-difluorohalobenzenes

The gas-phase copyrolysis of tetrafluoroethylene and buta-1,3-diene in a flow tube reactor at 490-510 degrees C gives 3,3,4,4-tetrafluorocyclohex-1-ene, which is selectively converted to 1-bromo- or 1-chloro-2,3-difluorobenzene via intermediate steps of halogenation and dehydrohalogenation [4].

References

[1] Volchkov N V, Lipkind M B, Nefedov O M, et al. Three-step regioselective synthesis of 2, 3-difluorohalobenzenes using tetrafluoroethylene and buta-1, 3-diene as starting building blocks[J]. Russian Chemical Bulletin, 2021, 70(5): 925-932.

[2] Radini I A, Hird M. The synthesis and mesomorphic properties of liquid crystals with bulky terminal groups designed for bookshelf geometry ferroelectric mixtures[J]. Liquid Crystals, 2009, 36(12): 1417-1430.

[3] Hudlicky T, Gonzalez D, Stabile M, et al. New metabolites from the microbial oxidation of fluorinated aromatic compounds[J]. Journal of fluorine chemistry, 1998, 89(1): 23-30.

[4] Volchkov N V, Lipkind M B, Nefedov O M, et al. Three-step regioselective synthesis of 2, 3-difluorohalobenzenes using tetrafluoroethylene and buta-1, 3-diene as starting building blocks[J]. Russian Chemical Bulletin, 2021, 70(5): 925-932.