Preparation of 1,4-diMeO-2,5-diBr-benzene

[Aurelius]

Method for the Preparation of 1,4-dimethoxy-2,5-dibromobenzene:

Methods of Prep:

1,4-dimethoxy-2,5-dibromobenzene has been prepared by the bromination of 1,4- dimethoxybenzene in acetic acid w/o using potassium acetate(1), bromination of 3-bromo-2,6-dimethoxybenzene (3) as well as diazotization followed by sandmeyer reaction of 5-amino-2-bromo-1,4-dimethoxybenzene (3).  The present procedure is a variant of direct bromination of 1,4-dimethoxybenzene in acetic acid.

Direct bromination of polyphenolic ethers w/o the use of trapping agent for hydrogen bromide usually results in poor yields.  Contamination from gummy side products makes the work-up tedious.  The present use of potassium acetate as  trap for the HBr considerably improves the products yield (from 40% reported (2) w/o the use of the trap to 72-75% in the present procedure).  The work-up is also considerably simplified.  Functionalization of the aromatic nucleus by bromine in poly phenolic ethers has considerable synthetic utility since the bromine atom is amenable to SN Ar substitutions, e.g. by cyano group, useful for infoduction of side chains(2)

Defense Research Lab. (1970)

1.   J. Habermann, Ber. 11: 1034 (1878); H.E. Ungnade and K. T. Zilch.  JOC 16:64 (1966).
2.   W. E. Noland and F. J. Baude, JOC 31, 332 (1966).
3.   L. Rubenstein, JOCS 127, 1998 (1925).

[foxy2]

Post 294110

(foxy2: "2,5-dibromo-1,4-hydroquinone synthesis", Novel Discourse)

Just thought I'd add this.

[GC_MS]

There is also "Simple and practical halogenation of arenes, alkenes and alkynes with hydrohalic acid/H2O2 (or TBHP)", N B Barhate et al, Tetrahedron 55 (1999) 11127-11142. It is mentioned on Rh's site.
Standard procure: N,N-dimethyl-(2-bromo-5-methoxy)benzamide: A solution of TBHP (70% aq, 0.15 mL, 1.17 mmol) was added to a cooled mixture of HBr (48% aq, 0.20 mL, 1.17 mmol) in MeOH (5 mL) and the mixture stirred for 5 min. To this solution N,N-dimethyl(3-methoxy)benzamide (0.21 g, 1.17 mmol) was added, stirred for 30 min and then refluxed for 6 h. On completion of the reaction (TLC) the solvent was evaporated and the product taken in 5 mL water, extracted with dichloromethane (3 x 15 mL) and residue was purified by flash column chromatography over silica gel (10% EtOAc in petroleum ether) to affor pure product as thick yellow oil (0.28 g. 98%)
1,4-dimethoxybenzene can be brominated following this procedure.
- TBHP (4.0 eq), HBr (4.0 eq) -> 2,5-dibromo-1,4-dimethoxybenzene, 98% yield
- H2O2 (4.0 eq), HBr (4.0 eq) -> 2,5-dibromo-1,4-dimethoxybenzene, 99% yield
- TBHP (1.0 eq), HBr (1.0 eq) -> 2-bromo-1,4-dimethoxybenzene, 89% yield

(TBHP = tert-butylhydroperoxide, 70%)

[Rhodium]

This article is referenced above in in

Post 398778

(Aurelius: "Preparation of 1,4-diMeO-2,5-diBr-benzene", Novel Discourse)

Substitution in Derivatives of Quinol Ethers
Leon Rubenstein

J. Chem. Soc. 127, 1998-2004 (1925)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/4-methoxyphenol.reimer-tiemann.pdf)

Synthesis of 2-Hydroxy-5-Methoxybenzaldehyde by the Reimer-Tiemann formylation of 4-Methoxyphenol, as well as several brominations and nitration of 2,5-Dimethoxybenzaldehyde, 2-Hydroxy-5-Methoxybenzaldehyde and other derivatives.