An efficient synthesis of peri-hydroxy aromatic compounds: A strong base-induced [4+2]cycloaddition of 4-phenylthio-substituted homophthalic anhydrides with various sulfinyl-substituted dienophiles

Article abstract of DOI:10.1055/s-1998-1642

As an extension of the strong base-induced [4+2]cycloaddition of homophthalic anhydrides studied previously, we found a general and versatile synthesis of p-phenylthio substituted phenols by the reaction of 4-phenylthio-substituted homophthalic anhydrides and various dienophiles. The use of the sulfinyl-substituted dienophile is essential to produce the desired reaction under mild conditions in good yield.

Full text of DOI:10.1055/s-1998-1642

292
LETTERS
SYNLETT
An Efficient Synthesis of peri-Hydroxy Aromatic Compounds: A Strong Base-Induced
[4+2]Cycloaddition of 4-Phenylthio-Substituted Homophthalic Anhydrides with Various
Sulfinyl-Substituted Dienophiles
Yasuyuki Kita,* Kiyosei Iio, Akiko Okajima, Yoshifumi Takeda, Ken-ichi Kawaguchi, Brendan A. Whelan, and Shuji Akai
Faculty of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka 565, Japan
Fax +81 6-879-8229; E-mail kita@phs.osaka-u.ac.jp
Received 28 November 1997
Abstract: As an extension of the strong base-induced [4+2]cyclo-
addition of homophthalic anhydrides studied previously, we found a
general and versatile synthesis of p-phenylthio substituted phenols by
the reaction of 4-phenylthio-substituted homophthalic anhydrides and
various dienophiles. The use of the sulfinyl-substituted dienophile is
essential to produce the desired reaction under mild conditions in good
yield.
As an extension of the strong base-induced [4+2]cycloaddition of
homophthalic anhydrides studied previously, we have studied the
reaction of 4-phenylthio-substituted homophthalic anhydrides (2a, b)
and various dienophiles leading to p-sulfenyl phenols. We now report a
general, versatile and regioselective synthesis of p-phenylthio-
substituted peri-hydroxy aromatic compounds (Method C) (Scheme 2).
6
The general and efficient synthesis of peri-hydroxy aromatic
compounds, which have useful biological activity, including anthra-
1,2
cyclines and fredericamycin A, is significant in organic synthesis.
Recently, we reported an aromatic Pummerer-type reaction of p-sulfinyl
phenols and p-sulfinyl-substituted peri-hydroxy aromatic compounds
3
leading to p-quinones and protected p-dihydroquinones. With respect
to the synthesis of the starting p-sulfinyl phenols, we have already
reported the following two methods: (1) the p-specific thiocyanation of
phenols using hypervalent iodine reagent and the conversion of the
thiocyanato group to the sulfinyl group by treatment with Grignard
reagent followed by oxidation with m-chloroperbenzoic acid (Method
Scheme 2
3c,4
A)
and (2) the oxidative intramolecular [4+2]cycloaddition of o-[(ω-
phenylthioethynyl)acyl]phenols followed by oxidation of the sulfenyl
group (Method B) (Scheme 1).
5
The starting 4-phenylthio-homophthalic anhydrides (2a, b) were readily
prepared from the corresponding homophthalic acid dimethyl esters (1a,
b) in 3 steps with 70-80% overall yields. Similar to the case of the
6a
corresponding homophthalic anhydride, the strong base-induced
cycloaddition of 2b with acetylenedicarboxylic acid diethyl ester
directly gave the desired p-phenylthio-substituted adduct (3b) in 58%
yield (Scheme 3).
Scheme 3
Next, we examined the regioselective synthesis of p-phenylthio-
substituted peri-hydroxy aromatic compounds using dienophiles
attached with various leaving groups. Although the reaction of 2 with
7
4a-c, 5a, 6a and 7a (X = Cl, Br, SPh) took a long time and gave the
desired products in low yields (runs 1-3, 5, 7, 9, 11 in Table 1), the
8
reaction of 2 with sulfinyl-substituted dienophiles (4d, 5b, 6b, 7b)
immediately occurred at r.t. and gave the desired products (8-12) in
9,10
good yields (runs 4, 6, 8, 10, 12).
These results are listed in Table 1.
Scheme 1

March 1998
SYNLETT
293
We applied this anionic cycloaddition to the synthesis of the ABCD-
ring analog of fredericamycin A. In the case of 7b, the reaction
smoothly occurred at r.t. to give 12 in 82% yield (run 12).
Chemistry; Sammes, P. G., Ed.; Halstead Press: New York; 1978;
Vol. 2; c) Oki, T.; Takeuchi, T. Yuki Gosei Kagaku Kyokaishi
1982, 40, 2-19; d) Tamura, Y.; Kita, Y. ibid. 1988, 46, 205-217;
e) Kita, Y.; Takeda, Y. Kagaku to Kogyo 1997, 71, 298-309.
Debenzylation of 12 cleanly occurred by treatment with BCl .
3
t
Sequential silylene-protection of both phenol groups with Bu Si(OTf)
2
2
(2) a) Pandey, R. C.; Toussaint, M. W.; Stroshane, R. M.; Kalita, C.
C.; Aszalos, A. A.; Garretson, A. L.; Wei, T. T.; Byrne, K. M.;
Geoghegan, R. F., Jr.; White, R. J. J. Antibiot. 1981, 34, 1389-
1401; b) Boger, D. L.; Hüter, O.; Mbiya, K.; Zhang, M. J. Am.
Chem. Soc. 1995, 117, 11839-11849 and references cited therein.
followed by oxidation of the phenylsulfenyl group gave 13 in 97%
overall yield. The aromatic Pummerer-type reaction of 13 provided the
3b
ABCD-ring analog 14 in good yield (Scheme 4).
(3) a) Akai, S.; Takeda, Y.; Iio, K.; Yoshida, Y.; Kita, Y. J. Chem.
Soc., Chem. Commun. 1995, 1013-1014; b) Kita, Y.; Takeda, Y.;
Iio, K.; Yokogawa, K.; Takahashi, K.; Akai, S. Tetrahedron Lett.
1996, 37, 7545-7548; c) Akai, S.; Takeda, Y.; Iio, K.; Takahashi,
K.; Fukuda, N.; Kita, Y. J. Org. Chem. 1997, 62, 5526-5536;
d) Kita, Y.; Takeda, Y.; Matsugi, M.; Iio, K.; Gotanda, K.;
Murata, K.; Akai, S. Angew. Chem. Int. Ed. Engl. 1997, 36, 1529-
1531.
Scheme 4
In conclusion, we have succeeded in developing a general and versatile
synthesis of p-regioselective phenylthio-substituted peri-hydroxy
aromatic compounds, whose structure is expected to receive various
modifications. In this cycloaddition, using sulfinyl-substituted
dienophile is crucial, and this method offers very mild reaction
conditions and the direct formation of the desired compound in good
yield.
(4) a) Kita, Y.; Okuno, T.; Egi, M.; Iio, K.; Takeda, Y.; Akai, S.
Synlett 1994, 1039-1040; b) Kita, Y.; Takeda, Y.; Okuno, T.; Egi,
M.; Iio, K.; Kawaguchi, K.; Akai, S. Chem. Pharm. Bull. in press.
(5) a) Kita, Y.; Okunaka, R.; Honda, T.; Shindo, M.; Tamura, O.
Tetrahedron Lett. 1989, 30, 3995-3998; b) Kita, Y.; Okunaka, R.;
Honda, T.; Kondo, M.; Tamura, O.; Tamura, Y. Chem. Pharm.
Bull. 1991, 39, 2106-2114; c) Akai, S.; Iio, K.; Takeda, Y.; Ueno,
H.; Kita, Y. Synlett 1997, 310-312.
Acknowledgment: This study was performed using Special
Coordination Funds of the Science and Technology Agency of the
Japanese Government.
(6) a) Tamura, Y.; Sasho, M.; Nakagawa, K.; Tsugoshi, T.; Kita, Y.
J. Org. Chem. 1984, 49, 473-478; b) Tamura, Y.; Fukata, F.;
Sasho, M.; Tsugoshi, T.; Kita, Y. ibid. 1985, 50, 2273-2277.
(7) X = Cl, Br; a) Banville, J.; Grandmaison, J. -L.; Lang, G.;
Brassard, P. Can. J. Chem. 1974, 52, 80-87; b) Cameron, D. W.;
Feutrill, G. I.; Griffiths, P. G.; Hodder, D. J. J. Chem. Soc., Chem.
Commun. 1978, 688-689; c) Roberge, G.; Brassard, P. J. Org.
References and Notes
(1) a) Thompson, R. H. Naturally Occurring Quinones; Academic
Press: New York, 1971; b) Arcamone, F. Topics in Antibiotics

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Chem. 1981, 46, 4161-4166; d) Echavarren, A.; Prados, P.; Fariña,
F. Tetrahedron 1984, 40, 4561-4567; e) Bauman, J. G.; Hawley,
R. C.; Rapoport, H. J. Org. Chem. 1985, 50, 1569-1573.
quenched with saturated aqueous NH Cl and AcOEt. The organic
4
layer was washed with saturated aqueous NaCl, dried (Na SO ),
2
4
and concentrated in vacuo. The residue was purified by column
chromatography (hexane-AcOEt) to give 12 (75 mg, 82%) as
(8) X = SOPh; a) Paquette, L. A.; Moerck, R. E.; Harirchian, B.;
Magnus, P. D. J. Am. Chem. Soc. 1978, 100, 1597-1599;
b) Danishefsky, S.; Harayama, T.; Singh, R. K. ibid. 1979, 101,
7008-7012; c) Kaydos, J. A.; Smith, D. L. J. Org. Chem. 1983, 48,
1096-1099; d) Kraus, G. A.; Woo, S. H. ibid. 1986, 51, 114-116.
yellow crystals: mp 164-165 °C (recryst. from CH Cl -Et O), IR
2
2
2
-1
1
(KBr) 2950, 1734, 1705, 1671, 1580 cm ; H NMR (CDCl ) δ
3
1.91-2.00 (8 H, m), 5.33 (2 H, s), 7.04-7.08 (3 H, m), 7.13-7.16 (3
H, m), 7.39-7.46 (3 H, m), 7.55 (2 H, d, J = 7.5 Hz), 7.62 (1 H, t, J
= 8.5 Hz), 8.49 (1 H, d, J = 8.5 Hz), 11.26 (1 H, s); Anal. Calcd for
(9) Typical procedure: Under nitrogen atmosphere, a mixture of 2b
(94 mg, 0.25 mmol) and NaH (60% in mineral oil, 11 mg, 0.27
mmol) in anhydrous THF (8 ml) was stirred at 0 °C for 1.5 h. A
solution of 7b (53 mg, 0.19 mmol) in anhydrous THF (8 ml) was
added to the mixture at 0 °C. The whole was allowed to warm to
room temperature, and stirred for 0.5 h. The reaction mixture was
C
H
O S: C, 74.98; H, 5.03; S, 6.67. Found: C, 74.63; H, 5.08;
30 24
4
S, 6.59.
1
(10) Satisfactory spectral data (IR, H NMR, HRMS) and/or elemental
analyses for unknown compounds (2, 3b, 4d, 5b, 7-12) were
obtained.