[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.

Aromatic Annulation.

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.

Alternative Reagents.

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.

Related Reagents.

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.

1. (a) Hauser, F. M.; Rhee, R. P. JOC 1980, 45, 3061. (b) Hauser, F. M.; Rhee, R. P. JOC 1978, 43, 178.
2. Kadiyala, V. S. N.; Murty, R. P.; Dutta, K.; Mal, D. SC 1990, 20, 1705.
3. (a) Hauser, F. M.; Prasanna, S. T 1984, 40, 4711. (b) Hauser, F. M.; Mal, D. JACS 1983, 105, 5688. (c) Hauser, F. M.; Prasanna, S.; Combs, D. W. JOC 1983, 48, 1328. (d) Hauser, F. M.; Prasanna, S. JACS 1981, 103, 6378. (e) Hauser, F. M.; Prasanna, S. JOC 1982, 47, 383.
4. Hauser, F. M.; Hewawasam, P.; Baghdanov, V. M. JOC 1988, 53, 223.
5. Hauser, F. M.; Prasanna, S. JACS 1981, 103, 6378.
6. Hauser, F. M.; Caringal, Y. JOC 1990, 55, 555.
7. (a) Kraus, G. A.; Sugimoto, H. TL 1978, 2263. (b) Kraus, G. A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.; Prugh, S. JOC 1983, 48, 3439.
8. (a) Li, T.-t.; Walsgrove, T. TL 1981, 22, 3741. (b) Russell, R. A.; Pilley, B. A.; Irvine, R. W.; Warrener, R. N. AJC 1987, 40, 311.
9. (a) Dodsworth, D. J.; Calcagno, M.-P.; Ehrmann, E. U.; Devadas, B.; Sammes, P. G. JCS(P1) 1981, 2120. (b) Dodd, J. H.; Weinreb, S. M. TL 1979, 3593. (c) Wildeman, J.; Borgen, P. C.; Pluim, H.; Rouwette, P. H. F. M.; van Leusen, A. M. TL 1978, 2213.

Charles W. Murtiashaw

Pfizer, Groton, CT, USA

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