Synthesis of unsymmetrical chiral triaza-18-crown-6 and diaza-12-crown-4 with a pendant group

Full text of DOI:10.1021/jo000766h

J . Org. Chem. 2000, 65, 7225-7227
7225
which was prepared from D-mannitol according to the
literature (Scheme 1, 2).9,10 The primary hydroxyl group
of glycerol 1 was selectively protected from the secondary
hydroxyl group with TBDPSCl and imidazole in DMF in
88% yield. Subsequent allylation of the secondary hy-
droxyl group gave fully protected glycerol 2 in 93% yield.
Conversion of the allyl group to hydroxyethyl group was
carried out in two stages: (i) dihydroxylation with OsO4-
NMO, and (ii) diol cleavage with Pb(OAc)4 followed by
in situ reduction with NaBH4, producing alcohol 3a in
overall 81% yield. Alcohol 3a was converted to the
corresponding tosylate 3b in 87% yield for the next chain
extension. Treatment of tosylate 3b with tosylamide 411
in the presence of K2CO3 in DMF produced the coupled
product 5a in 65% yield. Debenzylation of the benzyloxy
group in 5a and mesylation of the corresponding diol 5b
gave dimesylate 6 in 98% yield for two steps. Finally,
triaza-18-crown-6 8 was obtained in 45% yield by the
reaction of bis-sulfonamide 7 with dimesylate 6 in a two-
phase system consisting of benzene, aqueous LiOH, and
tetrabutylammonium iodide as phase-transfer catalyst.
An attempt to increase the coupling yield using NaOH
was not successful (12%). Deprotection of 8 with tetrabu-
tylammonium fluoride (TBAF) in THF gave 9 in 91%
yield.
The synthesis of diaza-12-crown-4 12, an analogue with
smaller ring size, is described in Scheme 2. Initially, we
studied the coupling between dimesylate 6 and benzyl-
amine with Na2CO3 in refluxing acetonitrile, an appar-
ently more direct approach to diaza-12-crown-4, but we
could not obtain the desired product in any appreciable
amounts. It was reasoned that the intramolecular cy-
clization at the sterically more-hindered mesylate site
was hampered. Therefore, we modified the synthetic
route to avoid this problem. Deprotection of the benzyl
group of 3a and subsequent tosylation gave ditosylate
10 in overall 78% yield. Coupling of this ditosylate with
tosylamide 7 in a two-phase system consisting of benzene,
aqueous LiOH, and tetrabutylammonium iodide as phase-
transfer catalyst produced diaza-12-crown-4 11 in 70%
yield. In this case, the template effect of lithium cation
presumably accounts for the good coupling yield. Depro-
tection of 11 with tetrabutylammonium fluoride (TBAF)
in THF gave 12 in 99% yield. The absolute stereochem-
istry of 12 was confirmed by single-crystal X-ray crystal-
lography.12
Syn th esis of Un sym m etr ica l Ch ir a l
Tr ia za -18-cr ow n -6 a n d Dia za -12-cr ow n -4
w ith a P en d a n t Gr ou p
Chi-Wan Lee,* Eun J in J ung, Seok J ong Lee,
Kyo Han Ahn,* and Kwang S. Kim*
Department of Chemistry, Center for Superfunctional
Materials, Pohang University of Science and Technology,
Pohang 790-784, Korea
chiwan@chem.postech.ac.kr
Received May 19, 2000
The aza-crown compounds have received continued
attention over the past years for their ability to form
complexes of metal cations, halide anions, and small
organic molecules.1 Crown ethers bearing pendant groups
are important intermediates for their immobilization on
polymers2 and transformation into more complex lariat
crown ethers3 such as ionizable crown ethers,4 bis-crown
ethers,5 and chromogenic crown ethers.6 Owing to Brad-
shaw and co-workers’ extensive works, racemates of
functionalized diaza-crown compounds7 and symmetrical
chiral crown compounds8 have been well described.
Unsymmetrical chiral aza-crown compounds, however,
have not been prepared. Here we describe the synthesis
of optically pure triaza-18-crown-6 and diaza-12-crown-4
with a hydroxymethyl pendant group as unsymmetrical
chiral crown compounds.
The synthesis of triaza-18-crown-6 9 was carried out
using (R)-1-benzylglycerol 1 as the starting material,
* To whom correspondence should be addressed. C.-W. Lee: Fax
82-562-279-8137.
(1) (a) Bradshaw, J . S.; Krakowiak, K. E.; Izatt, R. M. Aza-crown
Macrocycles; J ohn-Wiley & Sons: New York, 1993. (b) Izatt, R. M.;
Bradshaw, J . S.; Nielsen, S. A.; Lamb, J . D.; Christensen, J . J .; Sen,
D. Chem. Rev. 1985, 85, 271.
(2) (a) Montanari, F.; Landini, D.; Rolla, F. Top. Curr. Chem. 1982,
101, 149. (b) Montanari, F.; Tundo, P. J . Org. Chem. 1982, 47, 1298.
(c) Fukunishi, F.; Czech, B.; Regen, S. L. J . Org. Chem. 1981, 46, 1218.
(d) Anelli, P. L.; Czech, B.; Montanari, F.; Quici, S. J . Am. Chem. Soc.
1984, 106, 861.
(3) (a) Dishong, D. M.; Diamond, C. J .; Cinaman, M. I.; Gokel, G.
W. J . Am. Chem. Soc. 1983, 105, 586. (b) Ikeda, I.; Emura, H.; Okahara,
M. Bull. Chem. Soc., J pn. 1984, 57, 1612. (c) Nakatsuji, Y.; Nakamura,
T.; Okahara, M.; Dishong, D. M.; Gokel, G. W. J . Org. Chem. 1981,
46, 1218. (d) Goli, D. M.; Dishong, D. M.; Diamond, C, J .; Gokel, G. W.
Tetrahedron Lett. 1982, 23, 5243.
(4) (a) Bartsch, R. A.; Heo, G. S.; Kang, S. I.; Liu, Y.; Strzelbicki, J .
J . Org. Chem. 1982, 47, 457. (b) Koszuk, J . F.; Czech, B. P.; Walkowiak,
W.; Babb, D. A.; Bartsch, R. A. J . Chem. Soc., Chem. Commun. 1984,
1504. (c) Czech, B.; Son, B.; Bartsch, R. A. Tetrahedron Lett. 1983, 24,
2923. (d) Czech, B.; Kang, S. I.; Bartsch, R. A. Tetrahedron Lett. 1983,
24, 457.
(5) (a) Kimura, K.; Ishikawa, A.; Tamura, H.; Shono, T. J . Chem.
Soc., Perkin Trans. 2 1984, 447. (b) Kimura, K.; Tamura, H.; Shono,
T. J . Chem. Soc., Chem. Commun. 1983, 492. (c) Maeda, T.; Ouchi,
M.; Kimura, K.; Shono, T. Chem. Lett. 1981, 1573.
(6) (a) Nakamura, H.; Nishida, H.; Takagi, M.; Ueno, K. Bunseki
Kagaku 1982, 31, E131. (b) Nakamura, H.; Nishida, H.; Takagi, M.;
Ueno, K. Anal. Chim. Acta 1982, 139, 219.
(7) Bradshaw, J . S.; Krakowiak, K. E.; Bruening, R. L.; Tarbet, B.
J .; Savage, P. B.; Izatt, R. M. J . Org. Chem. 1988, 53, 3190. (b)
Krakowiak, K. E.; Bradshaw, J . S.; Forsnes, E. V.; Izatt, R. M. J .
Heterocycl. Chem. 1989, 26, 661. (c) Krakowiak, K. E.; Bradshaw, J .
S.; Izatt, R. M. J . Heterocycl. Chem. 1990, 27, 1011. (d) Anelli, P. L.;
Montanari, F.; Quici, S. J . Org. Chem. 1985, 50, 3453.
In summary, we have established a versatile synthetic
route to chiral aza-crown ethers with a sidearm. The
synthesized triaza-18-crown-6 and diaza-12-crown-4 are
potentially useful intermediates for the synthesis of
template-linked poly(aza-crown ethers) and related ana-
logues, which would be interesting hosts for studying
their amphi-ionophore properties.13
Exp er im en ta l Section
Gen er a l P r oced u r es. All reagents were commercial products
and were used without further purification. Flash column
chromatography was performed on 230-400 mesh silica gel. Low
(9) Amma, J .; Stille, J . K. J . Org. Chem. 1982, 47, 468.
(10) Steiner, O.; Tamm, C. Tetrahedron Lett. 1993, 34, 6729.
(11) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1988, 53, 2367.
(12) See the Supporting Information for the crystal structural data
of 12.
(8) (a) Bradshaw, J . S.; Huszthy, P.; McDaniel, C. W.; Zhu, C. Y.;
Dalley, N. K.; Izatt, R. M. J . Org. Chem. 1990, 55, 3129. (b) Huszthy,
P.; Oue, M.; Bradshaw, J . S.; Zhu, C. Y.; Wang, T.; Dalley, N. K.; Cutris,
J . C.; Izatt, R. M. J . Org. Chem. 1992, 57, 5383.
(13) Kim, K. S.; Cui, C.; Cho, S. J . J . Phys. Chem. 1998, 102, 461.
10.1021/jo000766h CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/19/2000

7226 J . Org. Chem., Vol. 65, No. 21, 2000
Notes
mmol) in 4% aqueous NaOH (40 mL) solution was added
dropwise with vigorous stirring while the temperature was kept
below 10 °C. The reaction mixture was stirred 0 °C for 30 min
and then at room temperature for 90 min. The pH of the reaction
mixture was adjusted to about 8 by adding solid ammonium
chloride, and it was extracted with ethyl acetate. The organic
layer was washed with 5% aqueous NaOH solution and then
brine. Drying over MgSO4, concentration, and purification by
Sch em e 1
flash chromatography (4:1, hexanes-ethyl acetate) afforded 3a
1
(9.8 g, 81%) as colorless oil. [R]23 -10.94 (c 10.05, CHCl3); H
D
NMR (CDCl3) δ 1.06 (s, 9H), 3.60-3.74 (m, 9H), 4.55 (s, 2H),
7.33-7.45 (m, 11H), 7.66-7.70 (m, 4H); 13C NMR (CDCl3) δ 19.1,
26.7, 62.0, 63.7, 70.3, 71.9, 73.4, 80.0, 127.6, 127.7, 128.3, 129.7,
133.1, 133.2, 135.5, 137.7; FAB-MS m/z 465.1 ([M + H]+, calcd
465.2).
(S)-1-Ben zyloxy-2-[(ter t-bu tyld ip h en ylsilyloxy)m eth yl]-
6-N-(p-tolu en esu lfon yl)-6-a za -3,9-d ioxa -11-u n d eca n ol (5a ).
A mixture of sulfonamide 4 (4.8 g, 18.3 mmol), tosylate 3b (11.3
g, 18.3 mmol), and anhydrous K2CO3 (7.6 g, 55 mmol) in DMF
(100 mL) was refluxed for 2 days with vigorous stirring. After
being cooled to room temperature, the solid was removed by
filtration, and the filtered solution was concentrated. The residue
was purified by column chromatography (1:1, hexanes-ethyl
acetate) to give 5a (8.4 g, 65%) as colorless oil. [R]23 -3.93 (c
D
11.2, CHCl3); 1H NMR (CDCl3) δ 1.07 (s, 9H), 2.41 (s, 3H), 3.38-
3.76 (m, 17H), 4.54 (s, 2H), 7.25-7.46 (m, 13H), 7.67-7.73 (m,
6H); 13C NMR (CDCl3) δ 19.6, 21.9, 27.2, 49.0, 49.2, 62.1, 63.7,
69.8, 70.1, 70.4, 72.7, 73.8, 80.4, 127.6, 128.00, 128.04, 128.1,
128.8, 130.0, 130.1, 133.75, 133.79, 136.0, 137.3, 138.6, 143.6;
FAB-MS m/z 706.3 ([M + H]+, calcd 706.3); HRMS calcd
706.3234 for C39H52NO7SSi ([M + H]+), found 706.3259.
(S)-2-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-4,10,16-t r is-
(p -t olu en esu lfon yl)-4,10,16-t r ia za -1,7,13-t r ioxa cyclooct a -
d eca n e (8). Bis-sulfonamide 7(0.1 g, 0.24 mmol) and dimesylate
6 (0.18 g, 0.24 mmol) in benzene (1.4 mL) are added to a
refluxing mixture of tetra-n-butylammonium iodide (25% mol),
7% aqueous lithium hydroxide (1.4 mL), and benzene (9 mL).
The vigorously stirred mixture is heated under reflux for 7 days,
the organic layer is separated, and the solvent is removed under
reduced pressure. The solid is washed with methanol and filtered
off. Purification by flash chromatography on silica gel (2:1,
Sch em e 2
hexanes-ethyl acetate) afforded 8 (0.1 g, 45%). [R]23 -15.7 (c
D
1
0.25: CHCl3); H NMR (300 MHz, CDCl3) δ 1.0 (s, 9 H), 2.3 (s,
3H), 2.42 (d, 6H), 2.9-3.0 (m, 1H), 3.2-3.6 (m, 23 H), 3.7 (t,
1H) 7.3-7.4 (m, 12 H), 7.6 (q, 10 H); 13C NMR (CDCl3, 75 MHz)
δ 19.1, 21.4, 26.7, 45.9, 49.3, 49.5, 49.7, 51.4, 63.5, 66.0, 69.5,
70.0, 70.5, 70.6, 70.8, 77.4, 80.0, 126.9, 127.1, 127.7, 129.6, 129.7,
129.8, 133.0, 135.4, 136.0, 136.3, 136.5, 143.2, 143.3; FAB-MS
m/z 991.39 ([M + H]+, calcd 991.35).
[4,10,16-Tr is(p-tolu en esu lfon yl)-4,10,16-tr ia za -1,7,13-tr i-
oxa cycloocta d ec-2-yl]m eth a n ol (9). A solution 58 mg (0.06
mmol) of 8 in 5 mL of THF was treated with 0.03 mL of a 1.0 M
solution of tetrabutylammonium fluoride in tetrahydrofuran at
room temperature for 3 h. The reaction mixture was dried over
MgSO4 and concentrated. Purification by flash chromatography
on silica gel (1:1, hexanes-ethyl acetate) afforded 9 (40 mg,
1
and high-resolution mass analyses were performed by Taejon
Analytical Laboratory of Korea Basic Science Institute. 1H NMR
spectra were recorded on 300 MHz NMR spectrometer, and
chemical shifts (δ) are in part per million relative to TMS.
(S)-1-O-Ben zyl-3-O-(ter t-b u t yld ip h en ylsilyl)-2-O-(2-h y-
d r oxyeth yl)glycer ol (3a ). To a solution of 2 (11.9 g, 25.9 mmol),
N-methylmorpholine N-oxide (4.7 g, 40 mmol), THF (40 mL),
t-BuOH (15 mL), and water (7 mL) at 0 °C was added OsO4 (2.6
g, 2.5 wt % solution in t-BuOH, 0.26 mmol, 1 mol %), and the
resulting mixture was stirred for 24 h at room temperature. The
reaction mixture was treated with a saturated aqueous NaHSO3
solution, and it was vigorously stirred for 1 h. The mixture was
poured into water and then extracted with CH2Cl2. The com-
bined organic layers were washed with brine, dried over MgSO4,
and concentrated to give the corresponding diol, which was
subjected to the next step without purification. To a THF (40
mL) solution of the above diol was added portionwise dry Pb-
(OAc)4 (11.5 g, 25.9 mmol) while the temperature was kept below
10 °C. The reaction mixture was stirred for 30 min with an ice-
water bath and additional 30 min without. After filtering
through Celite and cooling in an ice bath, NaBH4 (1.9 g, 50
91%): mp 69.0-70.3 °C; [R]23 -7.57 (c 0.81, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 2.44 (s, 9H), 3.24-3.40 (m, 12H), 3.53-
3.80 (m, 13 H), 7.32 (t, 6H), 7.68 (q, 6H); 13C NMR (CDCl3, 75
MHz) δ 21.4, 29.6, 49.4, 49.6, 49.8, 50.0, 50.1, 60.6, 68.5, 70.4,
70.5, 70.6, 70.9, 79.1, 126.9, 127.0, 127.1, 129.7, 129.8, 135.6,
135.8, 136.3, 143.4, 143.5, 143.6; FAB-MS m/z 754.25 ([M + H]+,
calcd 753.25); HRMS calcd 754.2502 for C34H47N3O10S3 ([M +
H])+, found 753.2511.
(S)-2-[(ter t-Bu t yld ip h en ylsilyloxy)m et h yl]-4,10-b is(p -
tolu en esu lfon yl)-4,10-d ia za -1,7-d ioxa cyclod od eca n e (11).
Bis-sulfonamide 7 (1.0 g, 4 mmol) and ditosylate 10 (1.7 g, 25
mmol) in benzene (15 mL) are added to a refluxing mixture of
tetra-n-butylammonium iodide (25% mol), 7% aqueous lithium
hydroxide (15 mL), and benzene (90 mL). The vigorously stirred
mixture is heated under reflux for 7 days, the organic layer is
separated, and the solvent is removed under reduced pressure.
The solid is washed with methanol and filtered off. Purification
by flash chromatography on silica gel (3:1, hexanes-ethyl
acetate) afforded 11 (1.3 g, 70%): mp 65.3-67.3 °C; [R]23D -16.7
(c 2.10, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.05 (s, 9H), 2.43
(s, 6H), 2.99-3.02 (m, 2H), 3.16-3.24 (m, 2H), 3.31-3.37 (m,

Notes
J . Org. Chem., Vol. 65, No. 21, 2000 7227
3H), 3.47-3.72 (m, 10H), 7.63-7.72 (m, 8H); 13C NMR (CDCl3,
75 MHz) 19.0, 21.2, 26.6, 49.7, 50.3, 51.3, 52.7, 58.0, 64.0, 69.3,
69.7, 70.6, 78.0, 78.8, 127.1, 127.3, 127.5, 127.6, 129.5, 129.6,
133.0, 133.1, 134.7, 135.4, 135.6, 143.1, 143.2; FAB-MS m/z 751.2
([M + H]+, calcd 751.04).
512.63, monoclinic, P21, a ) 6.0853(4) Å, R ) 90°, b ) 13.7666-
(9) Å, â ) 95.5070(10)°, c ) 14.4567(10) Å, γ ) 90°, V ) 1205.50-
(14) Å3, Z ) 2, Dcalcd ) 1.412 mg/m3, F(000) ) 544, µ(Mo KR) )
3.2 cm-1, λ ) 0.71073 Å, T ) 243 K, R1 ) 0.0417 and wR2 )
0.1121 for 2816 absorption corrected reflections with I > 2σ(I).
[4,10-Bis(p -t olu e n e su lfon yl)-4,10-d ia za -1,7-d ioxa cy-
clod od ec-2-yl]m eth a n ol (12). A solution 0.4 g (0.5 mmol) of
11 in 15 mL of THF was treated with 0.3 mL of a 1.0 M solution
of tetrabutylammonium fluoride in tetrahydrofuran at room
temperature for 3 h. The reaction mixture was dried over MgSO4
and concentrated. Purification by flash chromatography on silica
gel (1:4, hexanes-ethyl acetate) afforded 12 (0.27 g, 99%): mp
175.2-177.0 °C; [R]23D +15.6 (c 0.83, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 2.44 (s, 6H), 3.04-3.36 (m, 7H), 3.53-4.09 (m, 10 H),
7.29-7.34 (m, 4H), 67.69 (d, 4H); 13C NMR (CDCl3, 75 MHz) δ
21.4, 50.7, 51.4, 51.5, 51.9, 62.7, 67.3, 70.5, 71.0, 78.3, 127.31,
127.33, 129.7, 129.8, 134.8, 134.9, 143.5, 143.6; FAB-MS m/z
513.17 ([M + H]+, calcd 513.17); HRMS cacld 513.1729 for
Ack n ow led gm en t. This work was supported by
Creative Research Initiatives of the Korean Ministry of
Science and Technology. We thank Dr. J ongki Hong at
the Korea Basic Science Center for FAB and high mass
analysis.
Su p p or tin g In for m a tion Ava ila ble: The experimental
procedure, copies of 1H and 13C NMR spectra of all compounds,
and X-ray data for compound 12. This material is available
free of charge via the Internet at http://pubs.acs.org.
C
23H32N2O7S2 ([M + H])+, found 513.1744. Crystal Data: Mr )
J O000766H