on the nucleophilicity of primary sulfonamides11 allowed us
to start with a Ns-protected primary amine and later convert
it to the desired Ns-protected secondary amine. Alkylation
of 7 with Ns-protected 3-bromopropylamine12 afforded 10
(70% yield, Scheme 1, route B). Adding a methyl to the
sulfonamide nitrogen of 10 was achieved by using Fukuya-
ma’s method,13 methanol functionalization with triphe-
nylphosphine and diethyl azodicarboxylate in toluene,14 to
give 11 (94% yield). A Heck reaction produced methyl ester
12 (89% yield) from 11. Finally, hydrolysis of 12 provided
acid 13 (95% yield).
we observed with a similar aromatic system lacking the
4-iodo substituent.17 The ring’s apparently unusual reactivity
led us to investigate an alternative for converting 14 to 5.
Using catalytic amounts of Pd(Ph3P)4 and CuI in triethyl-
amine (Sonogashira conditions18), iodide 14 was readily
cross-coupled to ethynyltrimethylsilane to afford alkyne 15
(90% yield). The TMS-protected alkyne was subsequently
converted to alkynyl bromide 16 (91% yield) via a silver-
assisted desilylative bromination with NBS in acetone.19
Subsequent aminolysis of bromide 16 using 10-fold excess
of dimethylamine in THF-CH3CN followed by in situ
reduction of the intermediate with 1 M NaBH4 in MeOH
provided tertiary amine 17 (78% yield). The presence of
acetonitrile in the reaction mixture seemed to enhance the
reaction rate and minimize formation of undesired products.
Boc-protected amine 17 was converted to the dihydrochloride
salt of primary amine 5 upon treatment with excess 4 M
HCl in dioxane.20 LC-MS indicated a quantitative depro-
tection after 30 min at 0 °C.
The common part of both psammaplysenes, 5, was
prepared as shown in Scheme 2. O-Alkylation of 7 with Boc-
Scheme 2
The two-step transformation of 16 to 17 presumably
proceeds via an unusual ynamine intermediate (18, Scheme
3), which is quite different from the electron-deficient
Scheme 3
protected 3-bromopropylamine15 afforded 14 (96% yield).
Our initial attempts to cross-couple iodide 14 to an appropri-
ate organometallic reagent to directly introduce a saturated
two-carbon piece bearing a terminal masked aldehyde were
unsuccessful.16 The conventional Friedel-Crafts approach
was also abandoned due to the disappointing conversions
ynamines previously reported to be synthetically useful.21
Even though this elusive ynamine species was not directly
detected, an adduct heavier than 18 by one additional
dimethylamine unit was observed by LC-MS as the major
aminolysis product. An aliquot obtained from the reaction
mixture after full consumption of 16 was chromatographi-
(11) (a) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 4, 353. (b) Kan,
T.; Fukuyama, T. J. Synth. Org. Chem. Jpn. 2001, 59, 779.
(12) For preparation, see the Supporting Information.
(13) (a) Fukuyama, T.; Jow, C. K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373. (b) Fukuyama, T.; Cheung, M.; Jow, C. K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831.
(17) 2-Chloroacetyl-chloride was tried with catalyst AlCl3 in different
solvents, under various conditions.
(18) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467.
(14) Mitsunobu, O. Synthesis 1981, 1, 1.
(15) For preparation, see the Supporting Information.
(19) (a) Bowles, D. M.; Anthony, J. E. Org. Lett. 2000, 2, 85. (b) Tobe,
Y.; Nakagawa, N.; Kishi, J. Y.; Sonoda, M.; Naemura, K.; Wakabayashi,
T.; Shida, T.; Achiba, Y. Tetrahedron 2001, 57, 3629. (c) Tobe, Y.; Utsumi,
N.; Nagano, A.; Sonoda, M.; Naemura, K. Tetrahedron 2001, 57, 8075.
(20) Han, G.; Tamaki, M.; Hruby, V. J. J. Peptide Res. 2001, 58, 338.
(21) For a recent review on ynamine and ynamide research, see: Zificsak,
C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L. L.
Tetrahedron 2001, 57, 7575 and references therein.
(16) Allyl-Grignard and (1,3-dioxolan-2-ylmethyl)-Grignard reagent were
screened with catalysts NiCl2(dppp), Fe(TMHD)3, and PdCl2(dppf) under
various conditions. Analogous organozinc reagents were screened with
catalysts Pd(Ph3P)4, PdCl2[(o-tolyl)3P]2, and PdCl2(dppf). All cases suffered
from either unacceptable yields or poor regioselectivity for the p-iodide
position vs the o-bromide positions.
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