4-Bromo-2-fluorotoluene → Biphenyl

HRID 1648341Notes

Reaction equation

HRID 1648341 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4](F)[CH:3]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:5]1([C:8]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1

Participants

3

Reactant 1

HCID 1710404-Bromo-2-fluorotoluene

Product 1

HCID 7095Biphenyl

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Procedure

Scheme 1 illustrates the synthesis of compounds of formula (I) wherein V1 is Cl or Br and V2 is NHCOR22. The triazolinone intermediate 4 is synthesized by the general method described by L. Maravetz, U.S. Pat. No. 4,705,557 (1987) and G. Theodoridis, International Patent Application WO87/03782. The 2-halo-5-nitrophenylhydrazine 1 [generated from the hydrochloride, which is prepared from the 2-halo-5-nitroaniline according to H. Stroh and G. Westphal, Chem. Ber., 96, 184 (1963), by partitioning between diethyl ether and 1N sodium carbonate] is condensed with an α-keto acid 2 in aqueous acetic acid. The resulting hydrazone derivative 3 is heated in toluene with diphenylphosphoryl azide and triethylamine at a temperature up to 115° C. to yield the triazolinone 4. Separately, reaction of benzenesulfonyl chloride 5 with t-butylamine according to the procedure of J. G. Lombardino, J. Org. Chem., 36, 1843 (1971) yields the sulfonamide 6. Based on a literature method [M. J. Sharp, W. Cheng, and V. Snieckus, Tetrahedron Lett., 28, 5093 (1987)], metalation ortho to the sulfonamide is achieved with n-butyllithium in THF at -40° to 0° C. Then treatment with triisopropyl borate followed by acidic work-up affords the boronic acid 7. This tradergoes cross-coupling with 4-bromo-2-fluorotoluene in the presence of tetrakis(triphenylphosphine)palladium(0) according to literaure methods [M. J. Sharp, op. cit.; N. Miyamura, T. Yanagi, and A. Suzuki, Synth, Commun., 11, 513 (1981)] to give a biphenyl product. α-Bromination by use of bromine in carbon tetrachloride at reflux under irradiation with light yields the bromomethyl derivative 8. Treatment of the triazolinone 4 with sodium hydride in DMF followed by the biphenylmethyl bromide 8 yields the N4-alkylated triazolinone 9. Reduction of the nitro group with stannous chloride in the presence of concentrated aqueous hydrochloric acid and THF, followed by a sodium hydroxide work-up, provides the amine 10. Reaction of 10 with an appropriate acid chloride R22COCl in pyridine in the presence of DMAP affords the amide derivative 11. Altematively, 11 is obtained by coupling the amine 10 with the carboxylic acid R22CO2H in the presence of BOP reagent in methylene chloride. Next, the t-butyl protecting group is removed with amhydrous trifluoroacetic acid in the presence of anisole. The resulting sulfonamide is treated with sodium hydride in THF or DMF and then with di-t-butyl dicarbonate to yield the t-butyl sulfonylcarbamate 12. In a variation of the last step, di-t-butyl dicarbonate can be replaced by a branched C3 -C4 alkyl chloroformate to provide the corresponding branched C3 -C4 alkyl sulfonylcarbamate. ##STR6##

Sources & evidence

ORD record
ord-3f4549b6d8c14d559617d60e45232664
Source dataset
uspto-grants-1995_07
Patent number
US05436259

Reaction notes

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