[65131-09-1] · C15H12O5S · 7-Methoxy-3-(phenylsulfonyl)-1(3H)-isobenzofuranone · (MW 304.34)
(regioselective synthesis of 1,4-dihydroxy-2,3-disubstituted naphthalenes)
Physical Data: colorless solid; mp 176-177 °C.
Solubility: partially sol THF; sol acetone.
Analysis of Reagent Purity: 1H NMR (CDCl3) d 3.93 (s, 3H), 6.10 (s, 1H), 7.04 (d, J = 8 Hz, 1H), 7.40-7.92 (m, 7H).
Preparative Methods: ethyl 2-methoxy-6-methylbenzoate is oxidized via the dibromide to the corresponding 3-hydroxyisobenzofuranone, which is subsequently treated with thiophenol and catalytic acid. Oxidation to the sulfone is accomplished with either m-Chloroperbenzoic Acid or Hydrogen Peroxide.1a An alternative one-step method utilizing the requisite phthaldehydic acid has also been described.2
Handling, Storage, and Precautions: apparently stable at rt and requires no special handling or precautions.
7-Methoxy-3-(phenylsulfonyl)-1(3H)-isobenzofuranone (1) can be deprotonated at -78 °C with either Lithium Diisopropylamide or Lithium t-Butoxide to form a soluble yellow anion which can be utilized as an effective nucleophile in the Michael reaction. The initial anionic adduct cyclizes with concomitant elimination of benzenesulfinic acid to yield a 1,4-dihydroxynaphthalene which is unambiguously disubstituted at the 2- and 3-positions (eq 1).1b
The 1,4-dihydroxynaphthalene products are susceptible to air oxidation and are frequently protected as the 1,4-dimethoxy derivatives. Alternatively, they may be intentionally oxidized to the naphthoquinones. A variety of acyclic and cyclic Michael acceptors participate in this reaction and yields are generally good. A few representative examples are seen in Table 1.1b,3
In fact, (1) represents a group of reagents (2)-(6) all having the 3-(phenylsulfonyl)isobenzofuranone moiety and all capable of the aromatic annulation reaction previously discussed.1b,4-6
Under conditions similar to those described above, these compounds have been frequently utilized as building blocks for the synthesis of a wide range of molecules in the anthracyclinone family.
3-Cyanoisobenzofuranones have also been synthesized and shown to be useful in identical aromatic annulation reactions (eq 2).7 Moreover, in several direct comparisons of 3-cyano vs. 3-phenylsulfonyl, the cyano version generally provides higher yields of the desired product.8 Nevertheless, on a large scale the liability of cyanide waste streams could be an important negative factor.
Similar aromatic annulations have been reported with a number of conceptually related reagents,1b,9 the common thread of these methods being regioselective installation of substituents in the 2- and 3-positions of the newly formed naphthalene.
Charles W. Murtiashaw
Pfizer, Groton, CT, USA