Monoamides of 18-Crown-6-tetracarboxylic Acid
J . Org. Chem., Vol. 62, No. 18, 1997 6229
here, only two other exceptions to the rules above are
Attem p ted P r ep a r a tion of 16a . To a stirred solution of
dianhydride 4 (605 mg, 1.5 mmol) in dry THF (100 mL) was
added dropwise a solution of 15a (300 mg, 1.28 mmol) and
triethylamine (1.0 g, 10 mmol) in dry THF (50 mL), and the
resulting solution was stirred overnight. The reaction mixture
known: a symmetrical tetraamide from N,N-dioctyl-
amine18 and a pair of syn- and anti-diamide diacids also
from N,N-dioctylamine.19 Designs of future supra-
molecular targets based on 1 as a framework element
should humor its limitations.
was evaporated, and the residue was partitioned between
1
dilute aqueous acid and CHCl
3
. The H NMR spectrum of the
organic extract indicated predominantly diamides from inte-
gration of the aromatic and crown ether signals. The aqueous
extract was continuously extracted with CHCl overnight. The
3
Exp er im en ta l Section
Proton NMR spectra were recorded at 250 or 360 MHz in
continuous organic extract was analyzed by HPLC using a gel
CDCl
recorded at 62.89 or 90.57 MHz in CDCl
High-resolution EI mass spectra were recorded using
3
, CD
3
OD, or acetone-d
6
.
Carbon NMR spectra were
permeation column (Alltech; 500 Å, 5 mm column, 25 cm × 1
3
, CD OD, or acetone-
3
cm i.d., elution with CH OH at ∼30 atm, UV detection at 254
3
d
6
.
nm), and two large peaks were seen along with many smaller
ones. Samples of the two major fractions were isolated by
pooling the products from repeated injections onto this column.
One fraction contained very little material and was composed
of several compounds according to the 13C NMR spectrum. The
other fraction was identified as impure diamides (17a and
perfluorokerosene as standard. High-resolution LSIMS were
recorded with either glycerol or m-nitrobenzyl alcohol (NMBA)
as matrix and Cs/Na iodides as standard. Optical rotation
measurements were recorded using a low-volume (1.5 mL) cell
with a 10 cm path length and spectral grade methanol as
solvent. Dichloromethane was distilled before use. THF was
dried by refluxing over, then distilling from, K metal under a
1
18a ): H NMR (acetone-d ) showed the relative integrated
6
areas for the crown ether OCH peaks (16H) and the aromatic
2
dry N
2
atmosphere and was freshly dried for each procedure.
H peaks (4H per ring) to be 2:1, so there must be two aromatic
rings per crown ether: 13C NMR (acetone-d ) δ 33.4, 35.0, 51.1,
Solutions in organic solvents were dried using anhydrous
6
2
MgSO
were identical with previous samples.
-[(N-Meth yla m in o)m eth yl]ben zyl Alcoh ol (11). Com-
4
. Compounds 1 and 4 were prepared as previously and
53.0, 64.3, 70.5-71.4 (7 peaks), 78.9, 79.1, 81.6, 81.7, 127.5,
127.6, 127.8, 128.5, 136.5, 136.8, 142.3, 142.6, 169.5, 170.6.
N ,N ′-D ib e n zy l-2,12-d ic a r b a m o y l-(2R ,3R ,11R ,12R )-
1,4,7,10,13,16-h exa oxa cyclooct a d eca n e-3,11-d ica r b ox-
ylic Acid (17b). To a stirred solution of dianhydride 4 (500
mg, 1.23 mmol) in dry THF (50 mL) was added dropwise a
solution of benzylamine (132 mg, 1.23 mmol) and triethylamine
(1 mL, 7 mmol) in dry THF (25 mL), and the resulting solution
was stirred overnight. Water (25 mL) was then added, and
this solution was stirred for 0.5 h. The reaction mixture was
evaporated and then partitioned between dilute aqueous acid
4
pound 11 has been reported, but no preparation or character-
ization was provided.20 Our sample was prepared from methyl
2
1
4
-bromobenzoate, via the N-Me amide, transmetalation with
2
2
BuLi followed by carbonation to the benzoic acid, conversion
to the methyl ester, and reduction with excess LiAlH in THF
OD) δ 2.33 (s, 3H),
.65 (s, 2H), 4.58 (s, 2H), 4.88 (br s, 2H), 7.27-7.34 (m, 4H);
4
1
to give 11 as a colorless oil: H NMR (CD
3
3
1
3
C NMR (CD
HRMS (EI) calcd for C
51.10015 (49).
-[(N -Me t h yla m in o)m e t h yl]-O-(2-t e t r a h yd r op yr a n -
3
OD) δ 35.4, 56.0, 64.8, 128.0, 129.4, 139.1, 141.4;
9
H
13NO m/z 151.09979, found m/z
and CHCl . The organic layer was dried and evaporated to
3
1
1
give anti-diamide 17b (400 mg, 100%) as a colorless glass: H
4
NMR (CDCl ) δ 3.2-3.8 (m, 16H), 4.19 (s, 2H), 4.35 (s, 2H),
3
2
0
13
yl)ben zyl Alcoh ol (15a ). Compound 15a has been reported,
4.37 (m, 2H), 4.48 (m, 2H), 7.10-7.40 (m, 10H); C NMR
(CDCl ) δ 43.1, 69.2, 70.2, 70.3, 70.8, 79.9, 80.1, 127.3, 127.8,
but no preparation or characterization was provided. To a
solution of 11 as its HCl salt (520 mg, 2.78 mmol) in DMF (10
mL) were added dihydropyran (2 mL, 22 mmol) and conc HCl
3
128.5, 138.8, 170.3, 171.3; HRMS (-LSIMS, NMBA) calcd for
C H N O m/z 617.2347, found m/z 617.2336 (100).
3
0
37
2
12
(
1 drop), and the resulting solution was stirred at rt overnight.
The solution was evaporated to give a light brown solid. This
material was dissolved in CH OH (5 mL), added to a suspen-
sion of basic anion exchange resin in CH OH (100 mL), and
stirred overnight. The mixture was filtered and the filtrate
The aqueous extract was reduced to a small volume and
passed through a strong acid cation exchange resin eluting
with water. The eluate was evaporated to a colorless glass
which was identified as epimerized tetraacid 48 (290 mg, 0.66
3
3
1
mmol, 100%): H NMR (CD OD) δ 3.1-3.9 (m, 16H), 4.2-4.6
3
1
13
evaporated to give 15a as a colorless oil (400 mg, 61%):
NMR (CDCl
3
1
H
(m, 4H); C NMR (CD OD) δ 71.0-76.0 (several peaks), 80.8-
3
3
) δ 1.4-1.9 (m, 6H), 2.34 (s, 3H), 3.46 (m, 1H),
.65 (s, 2H), 3.83 (m, 1H), 4.40 (d, J ) 12 Hz, 1H), 4.63 (m,
H), 4.68 (d, J ) 12 Hz, 1H), 7.24 (m, 4H); 13C NMR (CDCl
81.8 (several peaks), 171-173 (several peaks); -LSIMS (NMBA)
-
20
m/e 439 (M - 1 ); [R]
D
) +7.3 (c 1.0, CH OH).
3
3
)
N-Ben zyl-2-ca r ba m oyl-(2R,3R,11R,12R)-1,4,7,10,13,16-
h exaoxacyclooctadecan e-3,11,12-tr icar boxylic Acid (16b).
To a stirred solution of dianhydride 4 (200 mg, 0.5 mmol) in
dry THF (1 mL) was added water (9 mL, 9 mg, 0.5 mmol),
and the resulting solution was stirred at room temperature
for 2 days. To this was added a solution of benzylamine (59
mg, 0.55 mmol) and triethylamine (220 mg, 2.2 mmol) in a
few milliliters of dry THF. A precipitate formed initially but
soon dissolved. The solution was stirred for 2 h and then
evaporated to a white foam. This was dissolved in a small
volume of water and passed through a small column of strong
acid cation exchange resin, eluting with water. The product
from this column was partitioned between water and CHCl3.
δ 19.2, 25.3, 30.4, 35.6, 55.5, 61.9, 68.4, 97.5, 127.8, 128.1,
39.0, 140.6; HRMS (+LSIMS, NMBA) calcd for C14
m/z 236.1652, found m/z 236.1683 (100).
1
H22NO
2
Typ ica l High -Dilu tion Ca p p in g Rea ction P r oced u r e:
Attem p ted P r ep a r a tion of 12 a n d 13. A solution of
triethylamine (23 mL, 16.8 g, 166 mmol) in dry THF (900 mL)
was stirred at maximum speed at room temperature under
2
an atmosphere of dry N . To this were added simultaneously,
via dual syringe pumps, a solution of 11 (1.66 mmol) in dry
THF (60 mL) and a solution of dianhydride 4 in dry THF (60
mL) at 1 mL/h over 2-3 days. After a further day, the reaction
mixture was evaporated, and the product was passed through
a strong acid cation exchange resin, eluting with 90% CH
water. The product was hydrolyzed by refluxing for 2 h in
3
OH/
The organic extract contained a ∼2:1 mixture of anti-diamide
1
17b and syn-diamide 18b (30 mg total, 0.05 mmol, 10%):
H
+
-
(
CH
3
)
4
N OH in CH
3
OH (2 M, 25 mL), and the ammonium
NMR (CDCl ) δ 3.2-3.8 (m, 16H), 4.2-4.6 (m, 8H), 7.1-7.3
3
(m, 10H); 13C NMR (CDCl ) δ 42.9, 43.2, 68.6-71.0 (7 peaks),
salt was removed with another strong acid cation exchange
column, eluting with water. In no instance were simple
product mixtures produced.
3
79.8, 79.9, 80.5, 81.7, 127.3, 127.8, 128.0, 128.3, 128.4, 128.5,
138.3, 138.8, 169.8, 170.2, 171.6, 171.9.
The aqueous extract was continuously extracted with CHCl
3
(
18) Bussmann, W.; Lehn, J .-M.; Oesch, U.; Plumere, P.; Simon, W.
Helv. Chim. Acta 1981, 64, 657.
19) Fyles, T. M.; McGavin, C. A.; Whitfield, D. M. J . Org. Chem.
984, 49, 753.
20) Nakata, H.; Suzuki, Y.; Shibata, M.; Takahashi, K.; Konishi,
H.; Takeda, N.; Tatematsu, A. Org. Mass Spectrom. 1990, 25, 649.
overnight. The continuous extract was dried and evaporated
to give monoamide 16b as a white foam (150 mg, 0.28 mmol,
(
6%): 1H NMR (acetone-d
5
6
) δ 3.40-3.85 (m, 16H), 4.35 (d, J
1
)
3 Hz, 1H), 4.38 (d, J ) 3 Hz, 1H), 4.47 (d, J ) 3 Hz), 4.49 (d,
(
J ) 3 Hz, 1H), 4.50 (m, 1H), 4.64 (m, 1H), 7.20-7.50 (m, 5H);
1
3
C NMR (acetone-d
6
) δ 43.3, 69.9-71.6 (7 peaks), 80.8, 80.9,
(
(
21) Hoffman, R. V.; Salvador, J . M. J . Org. Chem. 1992, 57, 4487.
22) Iwakura, Y.; Nishiguchi, T. J . Org. Chem. 1970, 35, 1591.
81.0, 81.4, 127.5, 128.8, 128.9, 140.5, 170.8, 171.2, 171.3, 171.6;