PAPER
Expedient Synthesis of 5,6-Dihydroxyindole
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(E)-3,4-Dihydroxy-b-nitrostyrene (2)
ZnSO4 (57.5 g, 0.2 mol) in 0.1 M phosphate buffer (pH 4, 200 mL).
The mixture was stirred for 3 h at 50°C and then was concentrated
under reduced pressure at r.t. to remove most of the EtOH. The res-
idue was extracted with EtOAc (3 î 100 mL), dried (Na2SO4) and
treated with hexane to precipitate 4b as a pale yellow solid which
was recrystallized from benzene/hexane (7.4 g, 90%); mp 114°C
(Lit.8 mp 115°C).
A mixture of 1 (20 g, 0.145 mol), NH4OAc (44.6 g, 0.57 mol),
MeNO2 (53 g, 0.87 mol) in HOAc (200 mL) was refluxed for 25
min. The solvent was then evaporated in a vacuum to give a dark red
oily residue, which was taken up in H2O (50 mL) and repeatedly ex-
tracted with Et2O (3 î 100 mL). Evaporation of the organic phase
gave 2 as bright orange crystals (25 g, 95%), mp 131.9–132.2oC.
1H NMR (acetone-d6): d = 6.96 (d, 1 H, J = 8.4 Hz), 7.25 (dd, 1 H,
J = 8.4, 2.0 Hz), 7.31 (d, 1 H, J = 2.0 Hz), 7.77 (d, 1 H, J = 13.6 Hz),
7.98 (d, 1 H, J = 13.6 Hz).
1H NMR (acetone-d6) d = 5.10 (s, 2 H), 5.12 (s, 2 H), 6.29 (m, 1 H),
7.08 (s, 1 H), 7.12 (m, 1 H), 7.19 (s, 1 H), 7.33 (m, 6 H), 7.50 (m, 4
H).
13C NMR (acetone-d6) d = 116.4, 116.7, 123.3, 124.7, 135.8, 140.4,
146.7, 150.6.
HRMS (EI): m/z calcd for C22H19NO2 (M+) 329.1417, found
329.1420.
HRMS (FAB): m/z calcd for C8H8NO4 (M+H+) 182.0453, found
182.0460.
Anal. calcd for C22H19NO2: C, 80.21; H, 5.82; N, 4.25. Found: C,
80.29; H, 5.85; N, 4.21.
Anal. calcd for C8H7NO4: C, 53.04; H, 3.95; N, 7.72. Found: C,
53.09; H, 3.89; N, 7.75.
5,6-Diacetoxyindole (4c)
To a solution of 3c12 (10 g, 0.032 mol) in CH2Cl2 (500 mL) was add-
ed a solution of Na2S2O4 (83.5 g, 0.48 mol) and ZnSO4 (73.6 g, 0.26
mol) in 0.1 M phosphate buffer (pH 4, 500 mL). The mixture was
stirred under Ar at 45°C for 4 h. After cooling to r.t., the organic
phase was separated and the aqueous layer was extracted with
EtOAc (3 î 200 mL). The combined organic phases were dried
(Na2SO4), concentrated under reduced pressure at r.t. and treated
with hexane to precipitate 4c as a chromatographically homogenous
greyish solid (5.2 g, 70 %); mp 132°C (Lit.12 mp 134–136°C).
(E)-4,5-Dihydroxy-2,b-dinitrostyrene (3a)
To a mixture of 2 (10 g, 0.055 mol) and ZnSO4 (79 g, 0.275 mol) in
0.1 M NaHCO3 buffer, (pH 8, 400 mL) and EtOH (80 mL) at 0°C
(ice bath) was added dropwise a solution of TNM (16.2 g, 0.08 mol)
in EtOAc (300 mL). The mixture was stirred in an ice bath for 40
min and then was concentrated under reduced pressure at r.t. to re-
move most of the EtOH. The residue was acidified to pH 4 and re-
peatedly extracted with Et2O (3 î 200 mL). Hexane was added to
the dried (Na2SO4) organic phase to precipitate an orange solid
which was recrystallized from H2O to yield 3a (8.75 g, 70%) as
bright yellow needles, mp 171–172oC (Lit.11 mp 169–171oC).
1H NMR (acetone-d6) d = 2.20 (s, 3 H), 2.22 (s, 3 H), 6.43 (m, 1 H),
7.23 (br s, 1 H), 7.32 (s, 1 H), 7.33 (m, 1 H).
HRMS (EI): m/z calcd for C12H11NO4 (M+) 233.0868, found
233.0869.
1H NMR (CD3OD): d = 7.27 (s, 1 H), 7.69 (s, 1 H), 7.75 (d, 1 H, J
= 13.4 Hz), 8.50 (d, 1 H, J = 13.4 Hz).
HRMS (FAB): m/z calcd for C8H7N2O6 (M+H+) 227.0304, found
Anal. calcd for C12H11NO4: C, 61.79; H, 4.76; N, 6.01. Found: C,
61.81; H, 4.73; N, 6.06.
227.0301.
Anal. calcd for C8H6N2O6: C, 42.48; H, 2.68; N, 12.39. Found: C,
42.56; H, 2.71; N, 12.33.
Acknowledgement
This work was supported by grants from MURST (Rome) and
Lawrence M. Gelb Research Foundation (Stamford, CT). We thank
Miss Silvana Corsani for technical assistance.
CAUTION: adviceable use of TNM suggests handling under an ef-
ficient hood.
5,6-Dihydroxyindole (4a)
A stirred mixture of 3a (8.0 g, 0.035 mol) in 0.1 M phosphate buffer
(pH 4, 100 mL) in a three-necked round-bottom flask, and a solution
of Na2S2O4 (60.9 g, 0.35 mol) and ZnSO4 (50.3 g, 0.175 mol) in 0.1
M phosphate buffer (pH 4, 100 mL) were fluxed with Ar separately
for 1 h. The latter solution was then rapidly added to the former via
a dropping funnel and the resulting mixture was stirred under Ar for
20 min at 40°C. Eventually, it was extracted with EtOAc (3 î 100
mL) under Ar and the combined extracts were carefully dried
(Na2SO4). Addition of benzene caused precipitation of 4a as a pale
yellow solid (2.7 g, 52%; > 98 % purity as determined by TLC and
NMR); mp 141–142oC (Lit.8 mp 141–142 oC).
References
(1) Prota, G. Melanins and Melanogenesis, Academic Press: San
Diego, 1992.
Prota, G. Fortschr. Chem. Organ. Naturstoffe 1995, 64, 93.
(2) Prota, G.; Brown, K. Cosmetics & Toiletries 1994, 109, 59.
Prota, G. Cosmetics & Toiletries 1996, 111, 43.
(3) Memoli, S.; Napolitano, A.; d’Ischia, M.; Misuraca, G.;
Palumbo, A.; Prota, G. Biochim. Biophys. Acta 1996, 1346,
61.
(4) Prota, G.; Misuraca, G. In Melanogenesis and Malignant Me-
lanoma: Biochemistry, Cell Biology, Molecular Biology, Pa-
thophysiology, Diagnosis and Treatment; Hori, Y.; Hearing,
V.J.; Nakayama, J., Eds.; Elsevier: Amsterdam, 1996; p 49.
(5) d'Ischia, M.; Napolitano, A.; Prota, G. Gazz. Chim. Ital. 1996,
126, 783.
1H NMR (acetone-d6) d = 6.23 (m, 1H), 6.89 (d, 1 H, J = 1 Hz), 6.98
(s, 1 H), 7.06 (dd, 1 H, J = 8.0, 6.0 Hz).
HRMS (EI): m/z calcd for C8H7NO2 (M+) 149.0477, found
149.0489.
Manini, P.; d’Ischia, M.; Milosa, M.; Prota, G. J. Org. Chem.
1998, 63, 7002.
(6) Beer, R.J.; Clarke, K.; Khorana, H.G.; Robertson, A. J. Chem.
Soc. 1948, 2223.
(7) Walker, G.N. J. Am. Chem. Soc. 1954, 77, 3844.
(8) Benigni, J.D.; Minnis, R.L. J. Heterocycl. Chem. 1965, 2, 387.
(9) Lutz, W.B.; McNamara, C.R.; Olinger, M.R.; Schmidt, D.F.;
Doster, D.E.; Fiedler, M.D. J. Heterocyclic Chem. 1984, 21,
1183.
Anal. calcd for C8H7NO2: C, 64.42; H, 4.74; N, 9.39. Found: C,
64.51; H, 4.79; N, 9.33.
NOTE: Failure to thoroughly deoxygenate and/or desiccate the or-
ganic extracts often resulted in darkening and more or less extensive
polymerization of the product with markedly decreased yield.
5,6-Dibenzyloxyindole (4b)
To a stirred mixture of 3b8 (10 g, 0.025 mol) in EtOH (200 mL) at
50oC was added a solution of Na2S2O4 (65.2 g, 0.375 mol) and
(10) Murphy, B.P.; Schultz, T.M. J. Org. Chem. 1985, 50, 2790.
Synthesis 1999, No. 5, 793–796 ISSN 0039-7881 © Thieme Stuttgart · New York