Synthesis of 6,7-dihydroxyoxindole (a subunit of paraherquamide A)

Full text of DOI:10.1021/jo9612640

8696
J . Org. Chem. 1996, 61, 8696-8697
Sch em e 1
Syn th esis of 6,7-Dih yd r oxyoxin d ole
(A Su bu n it of P a r a h er qu a m id e A)
Brad M. Savall and William W. McWhorter*
Animal Health Discovery Research, Pharmacia and
Upjohn Company, Kalamazoo, Michigan 49001
Received J uly 3, 1996
Paraherquamide A (1) and marcfortine A (2) are
alkaloids isolated from Penicillium paraherquei1 and
Penicillium roqueforti,2 respectively. Both of these natu-
ral products have potent anthelmintic activity,3 and they
are structurally very similar. In particular, they both
contain the 4,4-dimethyldioxepinooxindole ring system
that was first prepared by Williams and Cushing.4 The
Williams research group used this methodology in a total
synthesis of paraherquamide B.5
6,7-dimethoxyoxindole (5) by means of a modified Gas-
sman oxindole synthesis.6,8 Ethyl methylthioacetate was
chlorinated with sulfuryl chloride and reacted with 2,3-
dimethoxyaniline (4) in the presence of 1,8-bis(dimethyl-
amino)naphthylene9 to produce an azasulfonium salt,
which was in turn treated with triethylamine to bring
about the rearrangement of the azasulfonium ylide to
afford the ethyl ester of 2-amino-3,4-dimethoxy-R-(me-
thylthio)benzeneacetic acid. This carboxylic acid was
treated with glacial acetic acid to yield 3-(methylthio)-
6,7-dimethoxyoxindole (5) in 80% overall yield. The
presence of electron-donating substituents on the aniline
ring necessitate chlorination of the thioether rather than
the aniline.6b This oxindole 5 was desulfurized with
Raney nickel to give 6,7-dimethoxyoxindole (6) in 62%
yield. 6,7-Dimethoxyoxindole (6) was demethylated with
BBr3 in CH2Cl2 to produce 6,7-dihydroxyoxindole (7) in
86% yield.
We report a short and efficient synthesis of 6,7-
dihydroxyoxindole (7). We use the methodology of Gas-
sman and co-workers6 to form 6,7-dihydroxyoxindole (7)
in four steps with an overall yield of 35% from a
commercially available starting material as opposed to
the seven steps and 23% overall yield in the synthesis of
Williams and Cushing.4 6,7-Dihydroxyoxindole can be
converted to 4,4-dimethyldioxepinooxindole (8) by the
route developed by these researchers.4 4,4-Dimethyl-
dioxepinooxindole (8) or its precursors are envisoned to
be intermediates in a total synthesis of paraherquamide
A or marcfortine A.
Commercially available 2,3-dimethoxybenzoic acid (3)
was converted to 2,3-dimethoxyaniline (4) by the Yamada
modification of the Curtius rearrangement7 followed by
hydrolysis of the resulting urethane (Scheme 1). 2,3-
Dimethoxyaniline (4) was converted to 3-(methylthio)-
In summary, we prepared 6,7-dihydroxyoxindole (7) in
four steps with an overall yield of 35% from 2,3-
dimethoxybenzoic acid (3). Oxindole (7) can be converted
to 4,4-dimethyldioxepinooxindole (8) by the method of
Williams and Cushing.4
Exp er im en ta l Section
Gen er a l In for m a tion . 2,3-Dimethoxybenzoic acid was pur-
chased from Aldrich. All moisture-sensitive reactions were
conducted under N2. Unless specified, all commercially available
solvents and reagents were used without further purification.
Brine refers to a saturated aqueous sodium chloride solution.
Solvent removal was accomplished by a rotary evaporator
operating at house vacuum (40-50 Torr). Column chromatog-
raphy was performed with silica gel 60 (EM Science, 230-400
mesh ASTM). J values are given in Hz.
3-(Meth ylth io)-6,7-d im eth oxyoxin d ole (5). CH2Cl2 (200
mL, dried over 4 Å sieves) was cooled to -78 °C under N2. Ethyl
(methylthio)acetate (3.95 mL, 30.7 mmol) was added by syringe,
(1) Yamazaki, M.; Okuyama, E.; Kobayashi, M.; Inoue, H. Tetrahe-
dron Lett. 1981, 22, 135-136.
(2) Prange, T.; Billion, M.-A.; Vuilhorgne, M.; Pascard, C.; Polonsky,
J . Tetrahedron Lett. 1981, 22, 1977-1980.
(7) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc. 1972,
94, 6203. (b) White, J . D.; Yager, K. M.; Yakura, T. J . Am. Chem. Soc.
1994, 116, 1831-1838. (c) 2,3-Dimethoxyaniline is commercially
available from TCI-US.
(3) Ostlind, D. A.; Mickle, G. W.; Ewanciew, D. V.; Andriuli, F. J .;
Campbell, W. C. Res. Vet. Sci. 1990, 48, 260.
(4) Williams, R. M.; Cushing, T. D. Tetrahedron Lett. 1990, 31,
6325-6328.
(8) (a) Wierenga, W. J . Am. Chem. Soc. 1981, 103, 5621-5623. (b)
Warpehoski, M. A. Tetrahedron Lett. 1986, 27, 4103-4106. (c) Warpe-
hoski, M. A.; Gebhard, I.; Kelly, R. C.; Krueger, W. C.; Li, L. H.;
McGovern, J . P.; Praire, M. D.; Wicnienski, N.; Wierenga, W. J . Med.
Chem. 1988, 31, 590-603. (d) J ohnson, P. D.; Aristoff, P. A. J . Org.
Chem. 1990, 55, 1374-1375.
(5) (a) Cushing, T. D.; Sanz-Cervera, J . F.; Williams, R. M. J . Am.
Chem. Soc. 1993, 115, 9323-9324. (b) Cushing, T. D.; Sanz-Cervera,
J . F.; Williams, R. M. J . Am. Chem. Soc. 1996, 118, 557-579.
(6) (a) Gassman, P. G.; van Bergen, T. J . J . Am. Chem. Soc. 1974,
96, 5508-5512. (b) Gassman, P. G.; Gruetzmacher, G.; van Bergen, T.
J . J . Am. Chem. Soc. 1974, 96, 5512-5517.
(9) 1,8-bis(dimethylamino)naphthalene is sold by Aldrich under the
name Proton-Sponge.
S0022-3263(96)01264-9 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 24, 1996 8697
followed by sulfuryl chloride (2.47 mL, 30.7 mmol), and the
resulting mixture was stirred for 15 min. A solution of 4 (4.7 g,
31 mmol) and 1,8-bis(dimethylamino)naphthalene (6.58 g, 30.7
mmol) in CH2Cl2 (100 mL) was added over 1 h. After the
mixture was stirred for 2 h, a solution of triethylamine (4.28
mL, 30.7 mmol) in CH2Cl2 (10 mL) was added dropwise and the
reaction was allowed to warm to rt. This mixture was washed
with water (3 × 100 mL). The combined aqueous layers were
back-extracted with CH2Cl2 (100 mL). The combined organic
layers were washed with brine, dried over MgSO4, filtered, and
concentrated to yield ethyl 2-amino-3,4-dimethoxy-R-(methylth-
io)benzeneacetic acid as a brown oil. The crude material was
taken up in glacial acetic acid (200 mL) and stirred under N2
for 3 h. The acetic acid was removed by azeotropic rotary
evaporation using toluene to yield a brown tacky solid that was
suspended in Et2O (100 mL), stirred for 30 min, filtered, and
washed with cold Et2O. The crude product (5.6 g) was obtained
in 80% yield. An analytically pure sample was obtained by
recrystallization from toluene to yield orange crystals: mp 168-
170 °C dec; 1H NMR (300 MHz, CDCl3) δ 2.07 (3H, s), 3.88 (3H,
s), 3.88 (3H, s), 4.26 (1H, s), 6.60 (1H, d, J ) 8), 7.04 (1H, d, J
) 8), 7.69 (1H, br s); MS (EI, 70eV) m/ z (relative intensity) 241
(M+ + 2H, 1), 240 (M+ + H, 3), 239 (M+, 26). Anal. Calcd for
6,7-Dih yd r oxyoxin d ole (7). Under N2, 6 (2.00 g, 10.4 mmol)
was dissolved in dry CH2Cl2 (175 mL). The mixture was cooled
to -78 °C to give an orange suspension. Boron tribromide (52
mL, 52 mmol, 1.0 M in CH2Cl2) was added dropwise over 30
min. The reaction was warmed to rt over 90 min and was
maintained at rt for 1 h. The reaction mixture was poured over
ice/water (500 mL), and the organic layer was separated. The
aqueous layer was extracted with EtOAc (2 × 100 mL). The
aqueous layer was combined with the original organic layer and
again separated. The aqueous layer was again extracted with
EtOAc. The combined EtOAc extracts were dried over MgSO4
and concentrated to yield 7 (1.04 g, 61% yield) as a tan solid:
mp 237-245 °C dec. The aqueous layer was saturated with
NaCl and reextracted with EtOAc (4 × 50 mL). Additional 7
(0.43 g, 25% yield) was isolated from these extracts: 1H NMR
(300 MHz, CDCl3/CD3OD) δ 3.46 (2H, d, J ) 1), 6.52 (1H, d, J
) 8), 6.62 (1H, d, J ) 8); MS (EI, 70eV) m/ z (relative intensity)
167 (M+ + 2H, 1), 166 (M+ + H, 9), 165 (M+, 100); HRMS (EI)
m/ z calcd for C8H7NO3 (M+) 165.0426, found 165.0423. Anal.
Calcd for C8H7NO3: C, 58.18; H, 4.27; N, 8.48. Found: C, 57.98;
H, 4.46; N, 8.35.
Ack n ow led gm en t. We appreciate the assistance of
Elizabeth A. Walker with the preparation of this note.
We are grateful to the Structural, Analytical and
Medicinal Chemistry Department of Pharmacia and
Upjohn, Inc., for acquiring the mass spectra, infrared
spectra, ultraviolet spectra, and combustion analyses.
C
11H13NO3S: C, 55.21; H, 5.48; N, 5.85. Found: C, 55.18; H,
5.19; N, 5.49.
6,7-Dim eth oxyoxin d ole (6). Under N2, 5 (4.05 g, 16.9
mmol) was dissolved in ethanol (100 mL) and treated with a
large excess of Raney nickel. The suspension was refluxed for
2 h. Analysis (TLC, 1:1 EtOAc:Hex) showed the reaction to be
complete. The reaction was filtered through Celite and concen-
trated to give crude 6 (2.96 g) as an orange solid. The crude
product was recrystallized from EtOAc/hexane to give pure 6
(2.04 g, mp 188-191 °C dec) in 62% yield: 1H NMR (400 MHz,
CDCl3) δ 3.51 (2H, s), 3.87 (3H, s), 3.89 (3H, s), 6.55 (1H, d, J )
8), 6.89 (1H, d, J ) 8), 7.52 (1H, br s); MS (EI, 70eV) m/ z
(relative intensity) 194 (M+ + H, 11), 193 (M+, 100); HRMS (EI)
m/ z calcd for C10H11NO3 (M+) 193.0739, found 193.0740.
Su p p or tin g In for m a tion Ava ila ble: Copies of IR and UV
data for compounds 5-7 (1 page). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
J O9612640