5684
J . Org. Chem. 1996, 61, 5684-5685
A New On e-P ot Syn th esis of Dou ble-Ar m ed
Ion iza ble Cr ow n Eth er s Usin g th e Ma n n ich
Rea ction
Ki-Whan Chi,† Han-Chao Wei, Thomas Kottke, and
Richard J . Lagow*
Department of Chemistry and Biochemistry, University of
Texas at Austin, Austin, Texas 78712
Received February 16, 1996
F igu r e 1. ORTEP drawing of 1b.
Sch em e 1. P r ep a r a tion of 1
In tr od u ction
Double-armed crown ethers have been widely studied
as mimics of biological ionophores.1 Some of the azac-
rown ethers 1 with two ionizable arms exhibit favorable
complexing abilities toward many divalent metal ions.2
For example, the chromogenic crown ether 1h is known
to be a good selective reagent for the determination of
calcium ion concentration in blood serum.3 However, the
syntheses of various azacrown ethers 1 have been limited
since crown ethers analogous to 1 were obtainable only
by treatment of the appropriate benzylic halides or
carboxylic acid derivatives with 4,13-diaza-18-crown-6
(2)3,4 or N,N′-bis(methoxymethyl)-4,13-diaza-18-crown-6
with appropriate substituted phenols.5 In this paper, we
report a new one-pot method for syntheses of the double-
armed crown ethers 1 from 4,13-diaza-18-crown-6 (2) and
substituted phenols 3 (Scheme 1).
Resu lts a n d Discu ssion
The yields are good for 1a -f, although the yields drop
as strongly electron-withdrawing substituents are added,
as in 1g,h . The low yield of 1h is attributed to the poor
solubility of 3h in benzene as well as the relatively weak
nucleophilicity of 3h and its anion. Although the reaction
mechanism for our methodology is believed to be the
same as that of the usual Mannich reaction,6 our reaction
is quite sensitive to the particular solvent were used. For
example, the substitution of anhydrous ethanol for
benzene reduced the yields of 1a and 1c to 5% and 17%,
respectively. This result underscores the fact that the
selection of the right solvent is crucial for the successful
synthesis of the Mannich base via this method.
Crystals of 1b, 1c, and 1f suitable for single-crystal
structural determination7 were obtained by recrystalli-
zation from n-hexane and ethyl acetate mixture. The
crystal structures of 1b,c,f reveal that the hydroxyl
groups on both sidearms point to the center of azacrown
ring from opposite sides of the ring. This suggests that
the preferred conformations of 1b,c,f may be ideal for
axial complexation with a central guest cation.4b,d,8
(ORTEP drawings of 1b and 1f are given in Figures 1
and 2, respectively. That of 1c is available as supporting
information.)
† Visiting scholar from University of Ulsan, Republic of Korea.
(1) Tsukube, H. J . Coord. Chem. 1987, 16, 101.
(2) (a) Lindoy, L. F. The Chemistry of Macrocyclic Ligand Complexes;
Cambridge University: Cambridge, UK, 1989; p 116. (b) Hiraoka, M.
Crown Ethers and Analogous Compounds; Elsevier: Amsterdam, 1992;
pp 126-128.
(3) Nishida, H.; Tazaki, M.; Takagi, M.; Ueno, K. Mikrochim. Acta
1981, 281.
Additional host-guest chemistry studies of 1b,d ,f,g are
underway at this time, with results to be published.
(4) (a) Gustowski, D. A.; Gatto, V. J .; Mallen, J .; Echegoyen, L.;
Gokel, G. W. J . Org. Chem. 1987, 52, 5172. (b) Tsukube, H.; Takagi,
K.; Higashiyama, T.; Iwachido, T.; Hayama, N. J . Chem. Soc., Perkin
Trans. 1 1986, 1033. (c) Tsukube, H.; Yamashita, K.; Iwachido, T.;
Zenki, M. Tetrahedron Lett. 1988, 29, 569. (d) Tsukube, H.; Adachi,
H.; Morosawa, S. J . Chem. Soc., Perkin Trans. 1 1989, 89. (e) Tsukube,
H.; Uenishi, J .; Higaki, H.; Kikkawa, K.; Tanaka, T.; Wakabayashi,
S.; Oae, S. J . Org. Chem. 1993, 58, 4389.
(5) (a) Lukyanenko, N. G.; Pastushok, V. N.; Bordunov, A. V.
Synthesis 1991, 241. (b) Lukyanenko, N. G.; Pastushok, V. N.;
Bordunov, A. V.; Vetrogon, V. I.; Vetrogon, N. I.; Bradshaw, J . S. J .
Chem. Soc., Perkin Trans. 1 1994, 1489. (c) Bordunov, A. V.; Hellier,
P. C.; Bradshaw, J . S.; Dalley, N. K.; Kou, X.; Zhang, X. X.; Izatt, R.
M. J . Org. Chem. 1995, 60, 6097. (d) Bordunov, A. V.; Lukyanenko, N.
G.; Pastushok, V. N.; Krakowiak, K. E.; Bradshaw, J . S.; Dalley, N.
K.; Kou, X. J . Org. Chem. 1995, 60, 4912. (e) Zhang, X. X.; Bordunov,
A. V.; Bradshaw, J . S.; Dalley, N. K.; Kou, X.; Izatt, R. M. J . Am. Chem.
Soc. 1995, 117, 11507.
Exp er im en ta l Section
Gen er a l. To a solution of 4,13-diaza-18-crown-6 (2, 100 mg,
0.381 mmol) and paraformaldehyde (28 mg, 0.93 mmol) in dry
benzene (4 mL) was added the corresponding substituted phenol
3 (0.91 mmol) at rt. The resulting mixture was then heated and
held at reflux for 18-22 h. The solvent was removed in vacuo,
and the crude products were purified by flash chromatography.9
All the spectral data of products are in accordance with the
assigned structures of 1a -g. Data for 1H NMR (300 MHz), 13C
(7) The author has deposited atomic coordinates for these structures
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(8) Fronczek, F. R.; Gatto, V. J .; Minganti, C.; Schultz, R. A.;
Gandour, R. D.; Gokel, G. W. J . Am. Chem. Soc. 1984, 106, 7244.
(9) Silica gel (230-400 mesh) was deactivated by ∼2% triethylamine
in eluent solution (40-70% of ethyl acetate in hexane).
(6) (a) Tramontini, M.; Angiolini, L. Tetrahedron 1990, 46, 1791.
(b) Tramontini, M.; Angiolini, L. Mannich Base: Chemistry and Uses;
CRC Press: Boca Raton, FL, 1994; pp 17-20.
S0022-3263(96)00332-5 CCC: $12.00 © 1996 American Chemical Society
Chi, Ki-Whan
