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G. Amiet et al.
LETTER
NHAc
MeO
I
MeO
Li
N
Li
MeO
O
c
b
OBut
a
NHBOC
NHBOC
2
3
4
d
e
H
N
H
CH3
N
CH3
MeO
MeO
O
O
O
f
O
NH2
NHCHO
K2
K1
Scheme 2 (a) N-acetyl-2-azetidione; (b) 1.5 equiv 1,2-diiodoethane, 63%; (c) N-acetylpropargylamine, 5 mol% PdCl2 (PPh3)2, CuI 10 mol%,
Et3N, 76%; (d) HgSO4, 10% H2SO4, 41 °C, 59%; (e) HgSO4, H2O, HCOOH, CH2Cl2, r.t., 54%; (f) HCOOH, reflux, 54%.
(3) Odani, A.; Ferini-Strambi, L.; Zucconi, M.; Stankof, B.;
Frachini, F.; Smirne, S. Neuro Report 1994, 6, 132.
(4) (a) Reiter, R. J.; Menendez-Pelaez, A.; Poeggeler, B.; Tan,
D.-X.; Pablos, M. I.; Acuna-Castroviejo, D. Advances in
Pineal Research; Moller, M.; Pevet, P., Eds.; John Libbey
and Co.: London, 1994, 403. (b) Marshall, K.-A.; Reiter, R.
J.; Poeggeler, B.; Aruoma, O. I.; Halliwell, B. Free Radical
Biol. Med. 1996, 21, 307. (c) Cuzzocrea, S.; Zingarelli, B.;
Gilad, E.; Hake, P.; Salzman, A. L.; Szabo, C. J. Pineal Res.
1997, 23, 106. (d) Reiter, R. J.; Tang, L.; Garcia, J. J.;
Munos-Hoyos, A. Life Sci. 1997, 62, 853. (e) Antunes, F.;
Barclay, L. R. C.; Ingold, K. U.; King, M.; Norris, J. Q.;
Scaiano, J. C.; Xi, P. Free Radical Biol. Med. 1999, 26, 117.
(5) Zhang, H.; Squadrito, G. L.; Uppu, R.; Pryor, W. A. Chem.
Res. Toxicol. 1999, 12, 526.
There are no known morphophysiological barriers to me-
latonin and it is generally believed that it readily enters ev-
ery cell in the organism. To further investigate the claims
that 1, as an antioxidant, protects against damage caused
by free radicals, we required quantities of its metabolites,7
K1 and K2 for biological testing and analysis to determine
if they can serve as an index for melatonin’s antioxidant
activity.
Whilst Nb-acetyl-5-methoxykynurenamine has been pre-
viously prepared by the ozonolysis8 of 1 and the photosen-
sitized oxygenation of Nb-methoxycarbonyltryptamines9
also produced kynurenamines, our repeated efforts using
these approaches met with limited success.
(6) Turjanski, A. G.; Rosenstein, R. E.; Estrin, D. A. J. Med.
Chem. 1998, 41, 3684.
The synthesis (Scheme 2) commenced with the directed
ortho lithiation of 4-methoxy-N-(tert-butoxycarbon-
yl)aniline10 to give the dilithio intermediate 2. Quenching
with the lactam N-acetyl-2-azetidione, to give K2 was un-
successful.11 Lithium-iodine exchange produced 3,14 fol-
lowed by a Sonogashira reaction12 (the Pd0/Cu1-catalyzed
coupling of aryl halides with terminal acetylenes under
basic conditions) with N-acetylpropargylamine that re-
sulted in formation of the arylalkynamide 4.15 This com-
pound was directly converted into K1 by hydration of the
triple bond with catalytic mercuric sulfate in formic acid
solution, which also replaced the NHBOC group with
NHCHO substituent. Alternatively, when the triple bond
in 4 was hydrated with HgSO4 in 10% H2SO4, the -amin-
oketone derivative,13 K216,17was prepared, which when re-
fluxed with formic acid was converted into K1.16
(7) Metabolites of melatonin formed either in the peripheral or
CNS are potent inhibitors of the calcium-dependent release
of dopamine from retina. K2, (IC50: 10 nM) which is formed
in the CNS are potent activators of melatonin receptor sites
in retina.
(8) Hirata, F.; Hayaishi, O.; Tokuyama, T.; Senboh, S. J. Biol.
Chem. 1974, 249, 1311.
(9) Nakagawa, M.; Okajima, H.; Hino, T. J. Am. Chem. Soc.
1977, 99, 4424.
(10) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997,
62, 6507.
(11) Reaction of 2 with -butyrolactone gave the required keto-
alcohol product.
(12) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467. (b) Sonogashira, K. In Comprehensive
Organic Synthesis, Vol. 3; Trost, B. M.; Fleming, L., Eds.;
Pergamon Press: New York, 1991, Chap. 2.4.
(13) These compounds have been prepared form Weinreb
amides, see: (a) Gomtsyan, A. Org. Lett. 2000, 2, 11.
(b) Gomtsyan, A.; Koenig, R. J.; Lee, C.-H. J. Org. Chem.
2001, 66, 3613.
References
(1) (a) Sack, R. L.; Lewy, A. J.; Parrot, K.; Singer, C. M.;
McArthur, A. J.; Blood, M. L.; Bauer, V. K. Eur. J. Med.
Chem. 1995, 30, 661. (b) Dollins, A. B.; Zhdanova, I. V.;
Wurtman, R. J.; Lynch, H. J.; Deng, M. H. Proc. Natl. Acad.
Sci. U.S.A. 1994, 91, 1824. (c) Zhdanova, I. V.; Wurtman,
R. J.; Lynch, H. J.; Ives, J. R.; Dollins, A. B.; Morabito, C.;
Matheson, J. K.; Schomer, D. L. Clin. Pharmacol. Ther.
1995, 57, 552.
(14) To a solution of tert-butyl (4-methoxyphenyl) carbamate
(10.0 g, 44.82 mmol) in dry THF (112 mL) under N2 at
–78 °C, was added a solution of tert-butyllithium in pentane
(68.56 mL, 116.53 mmol). After 15 min the solution was
warmed to –20 °C and kept at that temperature for 2.5 h
whereupon a solution of 1,2-iodoethane (18.95 g, 67.23
mmol) in dry THF (40 mL) was added. The reaction mixture
was stirred at ambient temperature overnight. After
quenching with sat. aq Na2S2O3 solution (170 mL), the
reaction mixture was extracted with Et2O (3 270 mL). The
organic phase was washed with brine (160 mL), dried over
(2) (a) Petrie, K.; Conaglen, J. V.; Thompson, L.; Chamberlain,
K. Br. Med. J. 1989, 298, 705. (b) Arendt, J.; Aldhous, M.;
Marks, V. Annu. Rev. Chronopharmacol. 1986, 3, 49.
Synlett 2002, No. 3, 495–497 ISSN 0936-5214 © Thieme Stuttgart · New York