structurally interesting compounds were not reported until
the early 1980’s.5 The simple phthalate 5 was synthesized
only once. To prepare 5, Cava4 began with phthalic
anhydride. Treatment with PCl5 afforded 1,1,3,3-tetrachloro-
1,3-dihydroisobenzofuran 6. Its reaction with 1,1-dimethyl-
ethanethiol in trifluoroacetic acid gave, after rearrangement,
5. The same procedure was used to obtain the dimethoxy
compound 7 from the symmetrical 4,5-dimethoxyphthalic
anhydride, but this procedure cannot be expected to provide
only one thiothionoanhydride from an unsymmetrically
substituted phthalate.
a cyclized form 10. Esterification of the mixture of 9 and
10 gave mainly 11, but this was accompanied by 22% of
the cyclized form 12. Thioacetalization of 11, catalyzed by
ZnCl2, provided 13 in good overall yield. LDA was added
to a solution of 13 (containing 0.83 equiv of HMPA) at -78
°C. The mixture was allowed to attain room temperature,
and following aqueous workup and chromatography, the only
product was the dimethoxythiothionophthalic anhydride 147
in a yield of 85%.
We exploited the process outlined in Scheme 2 to effect
the first synthesis of a thiothionophthalic anhydride corre-
sponding to an unsymmetrically substituted phthalate (Scheme
3). Directed orthometalation of the acetal 8, derived from
It had been noted that 7 is less prone to reductive
dimerization than is 5.4 Similarly 14 proved to be stable over
an extended period at room temperature. Nevertheless, when
molten 14 was heated above 110 °C, dimeric compound 15
1
rapidly resolidified.8 The H NMR spectrum of 15 was
extremely similar to that of 14, but the melting point of 15
was above 310 °C. Also, the molecular ions were the base
peaks in the mass spectra of 14 and 15.
Scheme 3
In summary, fragmentation of the anion of the dithiolane
derivative of an R-carboxyethyl benzaldehyde leads to the
efficient production of a rare functional group variant, the
thiothionoanhydride.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for financial
support.
OL0066375
(4) Orange solid, mp >310 °C: 1H NMR (CDCl3, 300 MHz) δ 7.92
(2H, d, J ) 8.5 Hz), 7.20 (2H, d, J ) 8.5 Hz), 4.02 (3H, s), 4.00 (3H, s);
MS m/z (rel intensity) 418 (13, M+ + 2), 416 (100, M+), 401 (14), 242
(17), 200 (35), 183 (38), 170 (51), 143 (45), 130 (29), 41 (34), 28 (76).
(5) Raasch, M. S.; Huang, N.-Z.; Lakshmikantham, M. V.; Cava, M. P.
J. Org. Chem. 1988, 53, 891.
(6) (a) Kato, S.; Sugino, K.; Matsuzawa, Y.; Katada, T.; Noda, I.; Mizuta,
M.; Goto, M.; Ishida, M. Liebigs Ann. Chem. 1981, 1798. (b) Kato, S.;
Shibahashi, H.; Katada, T.; Takagi, T.; Noda, I.; Mizuta, M.; Goto, M.
Liebigs Ann. Chem. 1982, 1229. (c) Lakshmikantham, M. V.; Carroll, P.;
Furst, G.; Levinson, M. I.; Cava, M. P. J. Am. Chem. Soc. 1984, 106, 6084.
(7) Plaumann, H. P.; Keay, B. A.; Rodrigo, R. Tetrahedron Lett. 1977,
51, 4921.
3,4-dimethoxybenzaldehyde, provided the desired aldehydo-
acid 9.6 In solution, this compound was in equilibrium with
(8) Green-brown needles, mp 101-104 °C: IR (Nujol) 1713, 1568, 1265,
1
(1) Ozaki, Y.; Imaizumi, K.; Okamura, K.; Morozumi, M.; Hosoya, A.;
Kim, S.-W. Chem. Pharm. Bull. 1996, 44, 1785.
(2) In this reaction 0.8 equiv of HMPA was used. It was interesting that
2 was not produced when the amount of HMPA was raised to 3.2 equiv.
(3) (a) Gabriel, S.; Leupold, E. Chem. Ber. 1898, 31, 2646. (b) Toland,
W. G.; Campbell, R. W. J. Org. Chem. 1963, 28, 3124. (c) Markgraf, J.
H.; Heller, C. I.; Avery, N. L., III. J. Org. Chem. 1970, 35, 1588.
1235 cm-1; H NMR (CDCl3/CD3COCD3, 500 MHz) δ 7.92/7.88 (1H, d,
J ) 8.8 Hz), 7.19/7.50 (1H, d, J ) 8.8 Hz), 4.02/4.06 (3H, s), 4.00/3.96
(3H, s); 13C NMR (CDCl3, 125 MHz) δ 220.1 (0), 190.4 (0), 161.2 (0),
146.9 (0), 138.5 (0), 125.9 (0), 120.9 (1), 118.8 (1), 62.1 (3), 57.6 (3); MS
m/z (rel intensity) 242 (10, M+ + 2), 240 (100, M+), 225 (5), 207 (66),
179 (20), 121 (21), 120 (36), 106 (24), 104 (16), 94 (15), 93 (18), 78 (27),
69 (23).
3892
Org. Lett., Vol. 2, No. 24, 2000