Synthesis of lariat ethers with pendent amine, amide, O-benzylhydroxamate, and urethane groups

Article abstract of DOI:10.1002/jhet.5570400307

Synthetic routes to twenty-six new crown ether compounds with pendent amine, amide, O-benzylhydroxamate, and urethane groups are reported. The new lariat ether compounds are based on sym-dibenzo-16-crown-5, sym-dicyclohexano-16-crown-5, and 14-crown-4 sca

Full text of DOI:10.1002/jhet.5570400307

May-Jun 2003
443
Synthesis of Lariat Ethers with Pendent Amine, Amide,
O-Benzylhydroxamate, and Urethane Groups
Sadik Elshani, Hong-Sik Hwang, Michael J. Pugia,
Jan Krzykawski and Richard A. Bartsch*
Department of Chemistry and Biochemistry, Texas Tech University,
Lubbock, TX 79409-1061
Received December 2, 2002
Synthetic routes to twenty-six new crown ether compounds with pendent amine, amide, O-benzylhydrox-
amate, and urethane groups are reported. The new lariat ether compounds are based on sym-dibenzo-16-
crown-5, sym-dicyclohexano-16-crown-5, and 14-crown-4 scaffolds.
J. Heterocyclic Chem., 40, 443 (2003).
Introduction.
now been synthesized. New lipophilic lariat ether amines
were prepared as precursors for the synthesis of some of
the new lariat ether amides. Two lariat ethers with pendent
urethane groups were also prepared for comparison.
When combined with the previously reported
compounds, these lariat ethers provide systematic varia-
tion of several structural features. The synthesis of these
twenty-six new compounds is now described.
For over three decades, macrocyclic polyether com-
pounds (crown ethers) have been prepared and utilized in
alkali and alkaline earth metal cation determination and
separation due to their superior binding ability for these
metal ions [1]. Attachment of one or more side arms with
potential metal ion coordination sites produces complex-
ing agents that are known as lariat ethers [2]. Lariat ethers
are designed to enhance the cation binding ability of crown
ethers and also partly to mimic the dynamic complexation
processes exhibited by natural macrocyclic ionophores [3].
The coordinating properties of amide groups are well doc-
umented [4], and we and other researchers have prepared
crown ether, monoazacrown ether and diazacrown ether
compounds with pendent amide, N-alkylamide and N,N-
dialkylamide functionalities [5-11].
We reported earlier the synthesis of a large number of
lariat ether compounds with pendent oxyacetamide,
N-alkyl oxyacetamide and N,N-dialkyl oxyacetamide
groups attached to sym-(R)dibenzo-13-crown-4, sym-
(R)dibenzo-14-crown-4, sym-(R)dibenzo-16-crown-5, and
sym-(propyl)dicyclohexano-16-crown-5 scaffolds [10,11].
Subsequently, responses of these ionophores toward alkali
and alkaline earth metal cations, protons, and ammonium
ions in solvent polymeric membrane electrodes were
assessed [12,14]. Dibenzo-16-crown-5 compounds with
an N,N-dipentyloxyacetamide group attached to the central
carbon of the three-carbon bridge and a geminal alkyl
group of two or more carbon atoms have been found to be
Results and Discussion.
Synthesis of Lariat Ether Amines.
For the synthesis of lipophilic lariat ether amines, reduc-
tive amination [18,19] of sym-(keto)dibenzo-16-crown-5
(1) via a lariat ether imine intermediate 2, as shown in
Scheme 1, was envisioned. In attempted preparation of 2,
crown ether ketone 1 was treated with benzylamine and p-
toluenesulfonic acid in benzene with the co-product water
being removed by benzene azeotropic distillation with a
Dean-Stark apparatus. It was found that crown ether imine
+
excellent ionophores for Na -selective electrodes.
We also reported previously the preparation of a series of
lariat ether O-benzylhydroxamates [15,16]. Beside their
use as valuable intermediates for the preparation of lariat
ether hydroxamic acids, the responses of these ionophores
toward alkali and alkaline earth metal cations in solvent
polymeric membrane electrodes were assessed [16,17].
For further investigation of the influence of structural
variation for lariat ether amide and O-benzylhydroxamate
ionophores in solvent polymeric membrane electrodes,
new lariat ether compounds with pendent N-alkylamide,
N,N-dialkylamide and O-benzylhydroxamate groups have

444
S. Elshani, H.-S. Hwang, M. J. Pugia, J. Krzykawski and R. A. Bartsch
Vol. 40
2 could not be isolated due to its ready reaction with mois-
ture to reform 1. Without isolation, the imine intermediate
was treated with sodium cyanoborohydride in methanol at
pH 4 to give a low yield (2%) of desired amine 3.
A one-step reductive amination [20] of crown ether
ketone 1 with benzylamine, sodium cyanoborohydride,
and 5 N hydrochloric acid-methanol in methanol gave a
51% yield of amine 3 (Scheme 2). However, lariat ether
alcohol 4 was formed as a by-product and found to be dif-
ficult to separate from the desired product.
We believe that there is an equilibrium between ketone 1
and imine intermediate 2. Thus, reduction of the imine to
give the desired product 3 is in competition with reduction
of ketone 1 to give alcohol 4. If this rationalization is cor-
rect, a shift of the equilibrium to the imine intermediate 2
by removal of water produced in the imine-forming reac-
tion with a drying agent should increase the proportion of
desired product 3. In agreement, treatment of ketone 1
with benzylamine and 5 N hydrochloric acid-methanol in
methanol in the presence of 4 Å molecular sieves as the
drying agent followed by reduction with sodium
cyanoborohydride produced an 81% yield of the lariat
ether secondary amine 3 that was free from by-product 4
(Scheme 3). Subsequently, the same reaction conditions
were utilized with other primary amines to produce lariat
ether secondary amines 5-7 in good to very good yields.
from earlier work. By catalytic hydrogenation of 8, sym-
dicyclohexano-16-crown-5-oxyacetic acid (14) was pre-
pared. The sym-(R)dibenzo(or dicyclohexano)-16-crown-
5-oxyacetic acids were converted into the corresponding
acid chlorides by reaction with oxalyl chloride in benzene.
Subsequent treatment of the lariat ether acid chlorides with
the appropriate amine (ammonia for 19) in acetonitrile gave
the desired lariat ether amides 15-24 in very good yields.
In expansion of the previously reported lariat ether
amide series in which the structural change in geminal R
group was from hydrogen to linear alkyl groups of increas-
ing length to a branched alkyl group [10,11], this series
adds an aryl (phenyl) group. Lariat ether amides 20 and
23, in addition to containing R = decyl and phenyl group,
respectively, possess an additional phenyl group α to the
carboxamide function. Lariat ether amides 18 and 22 con-
tain phenyl and benzyl groups, respectively, on the amide
nitrogen instead of linear alkyl groups.
Amides 25 and 26 (Scheme 5) differ from previously
described lariat ether amides in that they contain a N-alky-
lamino group in addition to a N,N-dipentylamido function.
In the lariat ether amides described above and those
reported earlier [10,11], an oxygen atom connects the
functional side arm to the polyether ring. In contrast, for
25 and 26, a nitrogen atom links the sidearm to the
dibenzo-16-crown-5 unit. Lariat ether amines 6 and 7
were reacted with N,N-dipentylchloroacetamide in ace-
tonitrile at reflux in the presence of sodium bicarbonate
and a catalytic amount of sodium iodide to form amides 25
and 26, respectively. In contrast, reactions of 6 and 7 with
N,N-dipentylchloracetamide and sodium hydride in
tetrahydrofuran gave only recovered starting materials.
Synthesis of Lariat Ether Amides.
+
Another objective was to prepare potential Li -selective
lipophilic lariat ether 14-crown-4 amides 29 and 30
For the synthesis of lariat ether amides 15-24 (Scheme
4), the corresponding carboxylic acids 8-13 were available

May-Jun 2003
Synthesis of Lariat Ethers
445
(Scheme 6) for evaluation in polymeric membrane elec-
trodes. Reaction of lipophilic salicylic acid lariat ethers 27
and 28 with oxalyl chloride in benzene followed by reac-
tion with dioctylamine in tetrahydrofuran gave the
lipophilic ether amides 29 and 30 in high yields.
ionophores in solvent polymeric membrane electrodes,
new lariat ether compounds with an octyl group α to the
O-benzylhydroxamato group (37), a tert-butyl group on
each benzene ring (38), tolyl groups on the central carbon
of the three-carbon bridge (39-41), and a cyclohexyl group
in the same position (42) have been synthesized. Lariat
ethers 39-41 with tolyl groups were prepared for compari-
son of their potentiometric selectivities with those of (tri-
fluoromethyl)phenyl analogues in solvent polymeric mem-
brane electrodes [16]. This series will also allow the influ-
ence of different methyl group positions in 39-41 upon
their potentiometric selectivities in solvent polymeric
membrane electrodes to be determined.
Synthesis of Lariat Ether O-Benzylhydroxamates.
The lariat ether O-benzylhydroxamates 37-42 were pre-
pared from the corresponding lariat ether carboxylic acids
as shown in Scheme 7. First, the lariat ether carboxylic
acids 31-36 were converted into the corresponding acid
chlorides by reaction with oxalyl chloride in benzene at 0°,
followed by stirring at room temperature and finally at 60-
70°. Treatment of the lariat ether acid chlorides with O-
benzylhydroxylamine hydrochloride and triethylamine in
dry acetonitrile [15] afforded the lariat ether O-benzyl-
hydroxamates 37-42.
In earlier work, we reported the preparation of lariat
ether O-benzylhydroxamates with an alkyl or phenyl
group attached α to the O-benzylhydroxamate function or
on the polyether ring carbon geminal to the O-benzyl-
hydroxamate-containing side arm or to both positions
[15,16]. For further investigation of the influence of struc-
tural variation for lariat ether O-benzylhydroxamate
Synthesis of Lariat Ether Urethanes.
Two new crown ether compounds with pendent urethane
groups were synthesized by treating the lariat ether alcohol
with phenyl isocyanate as shown in Scheme 8. Such lariat
ether urethanes are of interest for comparison of their
metal ion-binding properties with those of lariat ether
amides and esters.
Structures of the twenty-six new lariat ether compounds
1
reported in this study were confirmed by H nmr and ir
1
spectra and by elemental analysis. In the H nmr spectra of

446
S. Elshani, H.-S. Hwang, M. J. Pugia, J. Krzykawski and R. A. Bartsch
Vol. 40
Perkin-Elmer Model 1600 FT-IR spectrophotometer. Proton
nuclear magnetic resonance (nmr) spectra were obtained with a
Bruker AF-200 (200 MHz) spectrometer. Elemental analyses
were performed by Desert Analytics Laboratory of Tucson,
Arizona.
lariat ethers with a geminal alkyl or aryl group on the cen-
tral carbon of the three-carbon bridge in dibenzo-16-crown-
5 lariat ethers, clearly discernable AB patterns were evident
for the diastereotopic methylene group hydrogens on the
three-carbon bridges which demonstrate conformational
restrictions of this structural unit on the nmr time scale [10].
General Procedure for the Synthesis of sym-(N-Alkylamino)-
dibenzo-16-crown-5 Compounds 3 and 5-7
To a solution of 0.50 g (1.56 mmole) of crown ether ketone 1,
a primary amine (8.7 mmole), and 1.0 g of molecular sieves (4 Å)
in absolute methanol (25 ml) was added 0.57 ml (2.9 mmole) of 5
N hydrochloric acid-methanol. The reaction mixture was stirred
at room temperature for 4 hours and cooled to -78°. Sodium
cyanoborohydride (55 mg, 0.90 mmole) was added and the mix-
ture was slowly warmed to -10° and stirred at -10° for 2 hours
and then at room temperature for 1 hour. The insoluble material
was filtered and the solvent was evaporated from the filtrate in
vacuo. Most of the excess of primary amine was removed in
vacuo with some heating. The residue was dissolved in
dichloromethane (20 ml) and washed with 5% aqueous sodium
hydroxide (10 ml), water (10 ml), and brine (10 ml). The organic
layer was dried over magnesium sulfate and evaporated in vacuo.
Column chromatography on silica gel with ethyl acetate/hexanes
(1:2) as eluent gave the product.
Further investigation of the potentiometric selectivities
of these lariat ether compounds in solvent polymeric mem-
brane electrodes, are in progress in our laboratories and the
results will be reported elsewhere.
sym-(N-Benzylamino)dibenzo-16-crown-5 (3).
This compound was obtained in 81% yield as a white solid with
mp 110-111°; ir (deposit from dichloromethane solution on a
sodium chloride plate): ν 3330 (NH), 1257, 1219, and 1121 (CO)
-1
1
cm ; H nmr (deuteriochloroform): δ 2.31 (br s, 1H), 3.45-3.51
EXPERIMENTAL
(p, 1H), 3.78-4.31 (m, 14H), 6.79-6.96 (m, 8H), 7.20-7.43 (m, 5H).
Anal. Calcd. for C
H NO : C, 71.70; H, 6.71; N, 3.22.
26 29 5
Found: C, 71.44; H, 6.73; N, 3.25.
Reagents and solvents were purchased from commercial
sources and used without further purification unless otherwise
noted. Tetrahydrofuran was dried and purified by distillation from
sodium under nitrogen with benzophenone ketyl as indicator.
Benzene was dried over sodium. Acetonitrile was dried over and
distilled from calcium hydride. Starting materials 1 [21], 4 [22], 8
[23], 9 and 10 [15], 11 [24], 12 and 13 [15], 27 and 28 [25], 31
[24], 32 [26], 33-35 [24], 36 [15], 43 [27] and N,N-dipentyl-2-
chloroacetamide [10] were prepared by reported procedures.
Melting points were determined with a Mel-Temp melting
point apparatus. Infrared (ir) spectra were recorded with a
sym-(N-Butylamino)dibenzo-16-crown-5 (5).
This compound was obtained in 50% yield as a white solid
with mp 83-84°; ir (deposit from dichloromethane solution on a
sodium chloride plate): ν 3332 (NH), 1257, 1224, and 1122 (CO)
-1
1
cm ; H nmr (deuteriochloroform): δ 0.95 (t, 3H, J = 6 Hz);
1.40-1.62 (m, 4H); 2.00 (br s, 1H); 2.77 (t, 2H, J = 6 Hz); 3.42-
3.45 (p, 1H); 3.93-4.31 (m, 12H); 6.83-7.00 (m, 8H).
Anal. Calcd. for C
H NO : C, 68.81; H, 7.78; N, 3.49.
23 31 5
Found: C, 68.57; H, 7.78; N, 3.39.

May-Jun 2003
Synthesis of Lariat Ethers
447
sym-(N-Octylamino)dibenzo-16-crown-5 (6).
Anal. Calcd. for C H NO •H O: C, 64.72; H, 7.74. Found:
27 37 7 2
C, 64.86; H, 7.45.
This compound was obtained in 74% yield as a white solid
with mp 57-58°; ir (deposit from dichloromethane solution on a
sodium chloride plate): ν 3324 (NH), 1257, 1225, and 1140 (CO)
cm ; H nmr (deuteriochloroform): δ 0.87 (t, 3H, J = 6 Hz);
1.12-1.32 (m, 10H), 1.55-1.58 (m, 2H); 1.97 (br s, 1H); 2.75 (t,
2H, J = 6 Hz); 3.38-3.44 (p, 1H); 3.86-3.97 (m, 4H); 4.00-4.30
(m, 8H); 6.82-7.00 (m, 8H).
N-Hexyl N-Methyl sym-Dibenzo-16-crown-5-oxyacetamide (16).
Column chromatography on alumina with dichloromethane as
eluent gave a 46% yield of colorless oil; ir (deposit from
dichloromethane solution on a sodium chloride plate): ν 1645
(C=O), 1261, 1120 (CO) cm ; H nmr (deuteriochloroform): δ
0.80-1.31 (m, 13H), 2.92 (s, 3H), 2.90-3.27 (m, 2H), 3.67-4.34
(m, 13H), 4.41 (s, 2H), 6.73-6.94 (m, 8H).
-1
1
-1
1
Anal. Calcd. for C
H NO : C, 70.87; H, 8.59; N, 3.06.
27 39 5
Found: C, 70.70; H, 8.53; N, 3.46.
Anal. Calcd. for C
Found: C, 60.89; H, 7.27.
H NO •CH Cl : C, 60.49; H, 7.16.
29 41 7 2 2
sym-(N-Dodecylamino)dibenzo-16-crown-5 (7).
This compound was obtained in 67% yield as a white solid
with mp 72-73°; ir (deposit from dichloromethane solution on a
sodium chloride plate): ν 3324 (NH), 1259, 1231, and 1124 (CO)
cm ; H nmr (deuteriochloroform): δ 0.88 (t, 3H, J = 6 Hz); 1.26
(br s, 18H), 1.55-1.58 (m, 2H); 1.97 (br s, 1H); 2.75 (t, 2H, J = 6
N-Dodecyl sym-Dibenzo-16-crown-5-oxyacetamide (17).
Column chromatography on silica gel with dichloromethane as
eluent gave a 79% yield of white solid with mp 99-100°; ir
(potassium bromide): ν 3390 (NH), 1675 (C=O), 1261, 1110
-1 1
-1
1
(CO) cm ; H nmr (deuteriochloroform): δ 0.82-1.39 (m, 23H),
3.00-3.34 (m, 2H), 3.75-4.32 (m, 15H), 4.30 (s, 2H), 6.76-6.97
(m, 8H), 7.50 (br s, 1H)).
Hz); 3.39-3.45 (p, 1H); 3.87-4.31 (m, 12H); 6.82-7.00 (m, 8H).
Anal. Calcd. for C
H NO : C, 72.48; H, 9.22; N, 2.73.
31 47 5
Found: C, 72.58; H, 9.48; N, 2.71.
Anal. Calcd. for C
H NO •H O: C, 67.21; H, 8.71. Found:
33 49 7 2
Preparation of sym-Dicyclohexano-16-crown-5-oxyacetic Acid
(14).
C, 67.09; H, 8.41.
N-Phenyl sym-Dibenzo-16-crown-5-oxyacetamide (18).
A mixture of lariat ether carboxylic acid 8 (6.60 g, 16.3
mmole), 0.70 g of 5% rhodium on alumina catalyst, 1.0 g of
glacial acetic acid and 320 ml of 1-butanol was hydrogenated at
65 °C under 500 psi of hydrogen for 16 hours. The mixture was
filtered through Celite and the filtrate was evaporated in vacuo to
give 6.80 g (100%) of 14 as a colorless oil; ir (neat): ν 3650-
Recrystallization from methanol produced a white solid in
93% yield with mp 164-165°; ir (deposit from dichloromethane
solution on a sodium chloride plate): ν 3339 (NH), 1677 (C=O),
1257, 1121 (CO) cm ; H nmr (deuteriochloroform): δ 3.85-
4.03 (m, 5H), 4.09-4.16 (m, 4H), 4.31 (s, 4H), 4.36 (s, 2H), 6.84-
7.04 (m, 8H), 7.19-7.30 (m, 2H), 7.55-7.68 (m, 3H), 9.47 (s, 1H).
-1
1
-1
1
2200 (OH), 1748 (C=O), 1267 and 1148 (CO) cm ; H nmr
(deuteriochloroform): δ 1.00-2.10 (m, 16H), 3.10-4.63 (m, 19H).
Anal. Calcd. for C
H NO : C, 67.63; H, 6.10; N, 2.92.
27 29 7
Found: C, 67.48; H, 6.06; N, 2.95.
Anal. Calcd for C
H O : C, 60.56; H, 8.71. Found: C,
21 36 8
60.41; H, 8.73.
sym-(Decyl)dibenzo-16-crown-5-oxyacetamide (19).
General Procedure for the Preparation of Lariat Ether Amides 15-
24, 29 and 30.
To the oily product, hexanes were added. Stirring for 2 hours
at room temperature to gave a white solid with mp 60-62° in 96%
yield; ir (deposit from dichloromethane solution on a sodium
chloride plate): ν 3471 (NH), 1686 (C=O) cm ; H nmr (deu-
teriochloroform): δ 0.85 (t, 3H, J = 6Hz), 1.28 (s, 16H), 1.88-
1.93 (m, 2H), 3.83-4.16 (m, 12H), 4.52 (d, 2H, J = 10 Hz), 4.57
(s, 2H), 5.57 (br s, 2H), 6.80-6.99 (m, 8H).
The lariat ether carboxylic acid (5.0 mmole) was added to 10
ml of dry benzene under nitrogen. After cooling to 0°, oxalyl
chloride (20 mmole) was added dropwise and the mixture was
stirred at room temperature for 1 hour and then warmed to 60° for
1 hour. The mixture was evaporated in vacuo and the resultant
acid chloride was dissolved in acetonitrile and the solution was
added dropwise to the corresponding amine (5.0 mmole) and tri-
ethylamine (5.0 mmole) in acetonitrile at 0° under nitrogen. (For
19 anhydrous ammonia was introduced into a cooled acetonitrile
solution of the corresponding acid chloride.) The mixture was
allowed to warm to room temperature, stirred for 12 hours, and
evaporated in vacuo. The residue was dissolved in ethyl acetate
and the solution was washed with 0.6 M hydrochloric acid, water,
0.6 M aqueous sodium bicarbonate, and water, and dried over
magnesium sulfate. Evaporation in vacuo gave the crude lariat
ether amide that was purified by column chromatography or
recrystallization.
-1
1
Anal. Calcd. for C
H NO : C, 68.48; H, 8.34; N, 2.58.
31 45 7
Found: C, 68.26; H, 8.41; N, 2.64.
N,N-Dipentyl α-[sym-(Decyl)dibenzo-16-crown-5-oxy]pheny-
lacetamide (20).
Column chromatography on silica gel with dichloro-
romethane-ethyl acetate (9:1) as eluent gave an oil in 96% yield;
ir (deposit from dichloromethane on a sodium chloride plate): ν
-1
1
1748 (C=O) 1256, 1122 (CO) cm ; H nmr (deuteriochloro-
form): δ 0.88 (t, 6H, J = 6 Hz), 1.10 (t, 3H, J = 7Hz), 1.24 (s,
20H), 1.26-1.29 (m, 8H), 2.04-2.09 (m, 6H), 3.88-4.04 (m, 8H),
4.11-4.27 (m, 2H), 4.49 (d, 1H, J = 10 Hz), 5.88 (s, 1H), 6.73-
6.93 (m, 8H), 7.25-7.33 (m, 3H), 7.52-7.55 (m, 2H).
N-Hexyl sym-Dibenzo-16-crown-5-oxyacetamide (15).
Anal. Calcd. for C
H NO : C, 74.27; H, 9.15; N, 1.84.
47 69 7
Column chromatography on silica gel with dichloromethane as
eluent gave an 81% yield of white solid with mp 102-104°; ir
(potassium bromide): ν 3333 (NH), 1668 (C=O), 1120 (CO)
cm ; H nmr (deuteriochloroform): δ 0.88-1.41 (m, 11H), 2.85-
3.30 (m, 2H), 3.75-4.32 (m, 13H), 4.36 (s, 2H), 6.75-6.95 (m,
8H), 7.58 (br s, 1H).
Found: C, 74.42; H, 8.91; N, 1.85.
N,N-Dipentyl sym-(2,2-Dimethylpropyl)dibenzo-16-crown-5-
oxyacetamide (21).
-1
1
Column chromatography on silica gel with dichloromethane
then ethyl acetate as eluent gave an 83% yield of white solid with

448
S. Elshani, H.-S. Hwang, M. J. Pugia, J. Krzykawski and R. A. Bartsch
Vol. 40
mp 75-76°; ir (deposit from dichloromethane on a sodium chlo-
Anal. Calcd. for C H NO : C, 73.59; H, 11.09. Found: C,
44 79 6
73.81; H, 11.24.
-1
1
ride plate): ν 1645 (C=O) 1256, 1121 (CO) cm ; H nmr (deu-
teriochloroform): δ 0.76-0.90 (m, 6H), 1.14-1.51 (m, 21H), 2.52-
2.64 (m, 1H), 3.21-3.36 (m, 4H), 3.88-3.92 (m, 4H), 4.13-4.16
(m, 4H), 4.22-4.55 (q, 4H), 4.67 (s, 2H), 6.79-6.97 (m, 8H).
General Procedure for the Preparation of Lariat Ether Amides 25
and 26.
Anal. Calcd. for C
70.49; H, 8.99.
H NO : C, 70.44; H, 9.03. Found: C,
A mixture of lariat ether amine 6 or 7 (0.98 mmole), N,N-
dipentylchloroacetamide (0.35 g, 1.50 mmole), sodium bicarbon-
ate (0.13 g, 1.55 mmole), and a catalytic amount of sodium iodide
in dry acetonitrile (20 ml) was refluxed for 48 hours. After cool-
ing to room temperature, the solvent was evaporated in vacuo.
The residue was dissolved in dichloromethane (30 ml), and the
solution was washed with water (30 ml) and then with brine (30
ml), dried over magnesium sulfate, and evaporated in vacuo.
Column chromatography on silica gel with ethyl acetate-hexanes
(1:4) and then with ethyl acetate-hexanes (1:2) gave the product
as a colorless oil.
36 55 7
N-Benzyl sym-(Phenyl)dibenzo-16-crown-5-oxyacetamide (22).
Column chromatography on silica gel with dichloromethane
then dichloromethane-ethyl acetate (9:1) as eluents and recrystal-
lization from ethyl acetate-hexanes produced a white solid in 70%
yield with mp 55-57°; ir (deposit from dichloromethane solution
on a sodium chloride plate): ν 3414 (NH), 1673 (C=O) 1256, 1124
-1
1
(CO) cm ; H nmr (deuteriochloroform): δ 3.86-3.96 (m, 2H),
3.97-4.03 (m, 2H), 4.04-4.18 (m, 4H), 4.36 (d, 2H, J = 10 Hz), 4.48
(d, 2H, J = 6 Hz), 4.74 (t, 4H, J = 4.5 Hz), 6.68-6.93 (m, 8H), 7.15-
7.35 (m, 5H), 7.38-7.43 (m, 3H), 7.62-7.65 (m, 2H), 10.01 (s, 1H).
N,N-Dipentyl [N-Octyl sym-amino)dibenzo-16-crown-5]-
acetamide (25).
Anal. Calcd. for C
H NO : C, 71.68; H, 6.19; N, 2.46.
34 35 7
Found: C, 71.41; H, 6.04; N, 2.45.
This compound was obtained as a colorless oil in 86% yield; ir
(deposit from dichloromethane solution on a sodium chloride
N,N-Dipentyl α-[sym-(Phenyl)dibenzo-16-crown-5-oxy)pheny-
lacetamide (23).
-1
1
plate): ν 1634 (C=O) 1256, 1142 (CO) cm ; H nmr (deuteri-
ochloroform): δ 0.80-0.92 (m, 9H), 1.27 (m, 18H), 1.53 (m, 6H),
2.85 (t, 2H, J = 6 Hz), 3.29 (t, 2H, J = 6 Hz), 3.44 (t, 2H, J = 6
Hz), 3.59-3.65 (m, 1H), 3.77 (s, 2H), 3.86-3.98 (m, 4H), 4.12-
4.16 (m, 4H), 4.30-4.33 (m, 4H), 6.80-6.99 (m, 8H).
An 87% yield of white solid with mp 69-71° was realized after
recrystallization from ethyl acetate-hexanes; ir (deposit from
dichloromethane on a sodium chloride plate): ν 1647 (C=O),
-1
1
1256, 1138 (CO) cm ; H nmr (deuteriochloroform): δ 0.70 (t,
6H, J = 6 Hz), 0.81-1.04 (m, 8H), 1.13-1.41 (m, 4H), 2.97-3.11
(m, 4H), 3.84-3.97 (m, 4H), 4.01-4.15 (m, 4H), 4.30 (d, 1H, J =
10 Hz), 4.59 (d, 1H, J = 10 Hz), 4.70 (d, 1H, J = 10 Hz), 4.78-
4.82 (d, 1H, J = 10 Hz), 5.84 (s, 1H), 6.72-6.91 (m, 8H), 7.28-
7.36 (m, 6H), 7.53 (d, 2H, J = 1.6 Hz), 7.93 (d, 2H, J = 1.5 Hz).
Anal. Calcd. for C
H N O : C, 71.52; H, 9.54; N, 4.28.
39 62 2 6
Found: C, 71.30; H, 9.35; N, 4.33.
N,N-Dipentyl [N-Dodecyl sym-(amino)dibenzo-16-crown-5]-
acetamide (26).
This compound was isolated as a colorless oil in 84% yield; ir
(deposit from dichloromethane solution on a sodium chloride
Anal. Calcd. for C
H NO : C, 74.22; H, 7.67; N, 2.01.
43 53 7
Found: C, 74.19; H, 7.28; N, 1.99.
-1
1
plate): ν 1641 (C=O) 1256, 1139, 1121 (CO) cm ; H nmr (deu-
teriochloroform): δ 0.80-0.92 (m, 9H), 1.25 (m, 26H), 1.53 (m,
6H), 2.85 (t, 2H, J = 6 Hz), 3.27 (t, 2H, J = 6 Hz), 3.45 (t, 2H, J =
6 Hz), 3.59-3.65 (m, 1H), 3.76 (s, 2H), 3.89-3.95 (m, 4H), 4.12-
4.16 (m, 4H), 4.31-4.34 (m, 4H), 6.80-6.99 (m, 8H).
N-Hexyl sym-Dicyclohexano-16-crown-5-oxyacetamide (24).
Column chromatography on silica gel with dichloromethane as
eluent gave a 56% yield of yellowish oil; ir (deposit from
dichloromethane solution on a sodium chloride plate): ν 3361
(NH), 1645 (C=O) 1261, 1120 (CO) cm ; H nmr (deuteriochlo-
roform): δ 0.72-1.51 (m, 27H), 3.15-4.24 (m, 17H), 7.67 (s, 1H).
-1
1
Anal. Calcd. for C
H N O : C, 72.64; H, 9.92; N, 3.94.
43 70 2 6
Found: C, 72.5.3; H, 9.70; N, 3.96.
Anal. Calcd. for C
62.90; H, 9.22.
H NO : C, 63.13; H, 9.67. Found: C,
27 45 7
General Procedure for the Preparation of Lariat Ether O-Benzyl-
hydroxamates 37-42.
Lipophilic Lariat Ether Amide 29.
The lariat ether carboxylic acid (5.0 mmole) was added to dry
benzene (10 ml) under nitrogen. After cooling to 0°, oxalyl chlo-
ride (2.50 g, 20 mmole) was added dropwise. The solution was
stirred at room temperature for one hour, heated at 60° for one
hour, and evaporated in vacuo to give the corresponding lariat
ether acid chloride that was used immediately in the next step.
O-Benzylhydroxylamine hydrochloride (800 mg, 5.0 mmole)
was suspended in dry acetonitrile (10 ml) and pyridine (0.80 ml,
10 mmole) was added. The mixture was cooled to 0° and an ace-
tonitrile solution of the lariat ether acid chloride was added drop-
wise. The mixture was allowed to warm to room temperature and
then stirred at room temperature for 24 hours. The mixture was
evaporated in vacuo and the residue dissolved in ethyl acetate.
The solution was washed with 0.6 N hydrochloric acid, water, 0.6
M aqueous sodium bicarbonate, and water, dried over magnesium
sulfate, and evaporated in vacuo to produce the lariat ether O-
benzyl-hydroxamate.
This compound was obtained in 95% yield as a colorless oil; ir
(deposit from dichloromethane solution on a sodium chloride
plate): ν 1640 (C=O), 1125 (CO) cm ; H nmr (deuteriochloro-
form): δ 0.82-2.00 (m, 53H), 2.52 (t, 2H, J = 6 Hz), 2.80-3.30
(m, 3H), 3.47-4.01 (m, 18H), 6.80 (d, 1H, J = 3 Hz), 6.99 (d, 1H,
J = 3 Hz), 7.1 (dd, 1H, J = 4 Hz).
-1
1
Anal. Calcd. for C
H NO : C, 73.59; H, 11.09. Found: C,
44 79 6
73.54; H, 11.14.
Lipophilic Lariat Ether Amide 30.
This compound was obtained in 96% yield as a colorless oil; ir
(deposit from dichloromethane solution on a sodium chloride
plate): ν 1640 (C=O), 1124 (CO) cm ; H nmr (deuteriochloro-
form): δ 0.80-2.10 (m, 51H), 2.30 (m, 1H), 2.51 (t, 2H, J = 6 Hz),
3.08 (m, 3H), 3.62-3.97 (m, 19H), 6.70 (d, 1H, J = 3 Hz), 6.99 (br
s, 1H), 7.00 (d, 1H, J = 3 Hz).
-1
1

May-Jun 2003
Synthesis of Lariat Ethers
449
O-Benzyl 2-(sym-Dibenzo-16-crown-5-oxy)decanohydroxamate
(37).
Hz), 4.89 (s, 2H), 4.92 (s, 2H), 6.69-6.96 (m, 8H), 7.21-7.35 (m,
9H), 9.47 (s, 1H).
Anal. Calcd. for C
Found: C, 70.32; H, 6.27; N, 2.14.
H NO : C,70.10; H, 6.22; N, 2.34.
35 37 8
Column chromatography on silica gel with dichloromethane-ethyl
acetate (9:1) as eluent and then recrystallization from methanol gave
a 76% yield of a white solid with mp 96-98°; ir (deposit from
dichloromethane solution on a sodium chloride plate): ν 3288 (NH),
O-Benzyl [sym-(Cyclohexyl)dibenzo-16-crown-5-oxy]acetohy-
droxamate (42).
-1 1
1689 (C=O) 1258, 1124 (CO) cm ; H nmr (deuteriochloroform): δ
Column chromatography on silica gel with dichloromethane-
ethyl acetate (9:1) as eluent and then recrystallization from ethyl
acetate-hexanes gave a 62% yield of white solid with mp 125-
127°; ir (deposit from dichloromethane solution on a sodium
chloride plate): ν 3336 (NH), 1696 (C=O) 1256, 1122 (CO) cm ;
H nmr (deuteriochloroform): δ 0.83-1.34 (m, 6H), 1.81-2.09
0.87 (t, 3H, J = 6 Hz), 1.26 (s, 10H), 1.67-1.91 (m, 4H), 3.82-3.98
(m, 4H), 4.01-4.19 (m, 8H), 4.65 (d, 1H, J = 10 Hz), 4.90 (s, 2H),
6.81-7.06 (m, 8H), 7.26-7.34 (m, 5H), 10.55 (s, 1H).
Anal. Calcd. for C
H NO : C, 69.61; H, 7.63; N, 2.25.
36 47 8
-1
Found: C, 69.22; H, 7.85; ; N, 2.44.
1
O-Benzyl (sym-Di[4(5)-tert-butylbenzo]-16-crown-5-oxy)aceto-
hydroxamate (38).
(m, 5H), 3.81-3.92 (m, 4H), 4.01-4.16 (m, 6H), 4.57 (d, 2H, J =
11 Hz), 4.85 (d, 4H, J = 15 Hz), 6.79-6.98 (m, 8H), 7.26-7.32 (m,
5H), 9.35 (s, 1H).
Recrystallization from pentane provided a white solid with mp
55-57° in 75% yield; ir (deposit from dichloromethane solution on
a sodium chloride plate): ν 3276 (NH), 1695 (C=O) 1267, 1145
Anal. Calcd. for C
H NO : C, 69.02; H, 6.93; N, 2.37.
34 41 8
Found: C, 69.23; H, 6.97; N, 2.22.
-1
1
(CO) cm ; H nmr (deuteriochloroform): δ 1.27 (s, 18H), 3.88-
3.90 (m, 4H), 4.11-4.28 (m, 8H), 4.35 (s, 2H), 4.92 (s, 2H), 6.77-
6.88 (m, 4H), 6.98-7.00 (m, 2H), 7.22-7.34 (m, 5H), 10.40 (s, 1H).
General Procedure for the Preparation of Lariat Ether Urethanes
44 and 45.
To a solution of the lariat ether alcohol (2.0 mmole) in 15 ml of
benzene (for 44) or pyridine (for 45) was added phenyl iso-
cyanate (0.26 g, 2.2 mmole) in 5 ml of pyridine. The reaction
mixture was stirred at 115° for 5 hours. The solvent was evapo-
rated in vacuo and the residue was purified by column chro-
matography on silica gel with dichloromethane then
Anal. Calcd. for C
H NO : C, 69.61; H, 7.63; N, 2.25.
36 47 8
Found: C, 69.32; H, 7.62; ; N, 2.22.
O-Benzyl [sym-(2-Tolyl)dibenzo-16-crown-5-oxy]acetohydroxa-
mate (39).
Column chromatography on silica gel with dichloromethane-
ethyl acetate (9:1) as eluent and then recrystallization from ethyl
acetate-hexanes gave a 68% yield of a white solid with mp 68-
70°; ir (deposit from dichloromethane solution on a sodium chlo-
1
dichloromethane-ethyl acetate (3:1) as eluents. Since the H nmr
spectrum showed the presence of residual diphenylurea, the prod-
uct was washed with cold diethyl ether (3x10 ml) to give the pure
lariat ether urethane.
-1
1
ride plate): ν 3327 (NH), 1685 (C=O) 1256, 1123 (CO) cm ; H
nmr (deuteriochloroform): δ 2.50 (s, 3H), 3.84-3.88 (m, 2H),
3.99-4.06 (m, 4H), 4.12-4.16 (m, 4H), 4.48 (d, 2H, J = 10 Hz),
4.72 (d, 2H, J = 10Hz), 4.74 (s, 2H), 6.73-6.95 (m, 8H), 7.19-7.31
(m, 8H), 7.58 (m, 1H), 9.50 (s, 1H).
N-Phenyl sym-Dibenzo-16-crown-5 Carbamate (44).
This compound was obtained in 89% yield as a white solid
with mp 133-135°; ir (deposit from dichloromethane solution on
a sodium chloride plate): ν 3352 (NH), 1695 (C=O) 1257, 1125
Anal. Calcd. for C
H NO : C,70.10; H, 6.22; N, 2.34.
35 37 8
-1
1
(CO) cm ; H nmr (deuteriochloroform): δ 3.89-3.93 (m, 4H),
4.12-4.16 (m, 4H), 4.43-4.46 (m, 4H), 6.80-7.07 (m, 8H), 7.28-
7.42 (m, 5H), 10.2 (s, 1H).
Found: C, 70.32; H, 6.27; ; N, 2.14.
O-Benzyl [sym-(3-Tolyl)dibenzo-16-crown-5-oxy]acetohydroxa-
mate (40).
Anal. Calcd. for C
H NO •CH Cl : C, 66.13; H, 5.79.
26 27 7 2 2
Found: C, 66.19; H, 5.61.
Column chromatography on silica gel with dichloromethane-
ethyl acetate (9:1) as eluent and recrystallization from ethyl
acetate-hexanes produced a 52% yield of white solid with mp
118-120°; ir (deposit from dichloromethane solution on a sodium
N-Phenyl sym-(Propyl)dibenzo-16-crown-5 Carbamate (45).
This compound was isolated in 92% yield as a white solid with
mp 119-121°; ir (deposit from dichloromethane solution on a
sodium chloride plate): ν 3349 (NH), 1692 (C=O) 1255, 1121
-1
chloride plate): ν 3340 (NH), 1693 (C=O) 1255, 1124 (CO) cm ;
1
H nmr (deuteriochloroform): δ 2.40 (s, 3H), 3.84-3.88 (m, 2H),
-1
1
(CO) cm ; H nmr (deuteriochloroform): δ 0.99 (t, 3H, J = 6
Hz), 1.48-1.60 (m, 2H), 2.25-2.34 (m, 2H), 3.90-3.95 (m, 4H),
4.12-4.16 (m, 4H), 4.45 (d, 2H, J = 10 Hz), 4.70 (d, 2H, J = 10
Hz), 6.79-7.05 (m, 8H), 7.27-7.36 (m, 5H), 10.24 (s, 1H).
4.03-4.17 (m, 6H), 4.25 (d, 2H, J = 12 Hz), 4.72 (d, 2H, J = 10
Hz), 4.82 (s, 2H), 4.89 (s, 2H), 6.67-6.94 (m, 8H), 7.23-7.35 (m,
9H), 9.51 (s, 1H).
Anal. Calcd. for C
H NO : C,70.10; H, 6.22; N, 2.34.
35 37 8
Anal. Calcd. for C
H NO : C, 68.62; H, 6.55. Found: C,
29 37 7
Found: C, 70.09; H, 6.34; N, 2.27.
68.77; H, 6.43.
O-Benzyl [sym-(4-Tolyl)dibenzo-16-crown-5-oxy]acetohydroxa-
mate (41).
Acknowledgement.
This research was supported by The Welch Foundation (Grant
D-775 to RAB).
Column chromatography on silica gel with dichloromethane-
ethyl acetate (9:1) as eluent and then recrystallization from ethyl
acetate-hexanes provided a 64% yield of a white solid with mp
66-68°; ir (deposit from dichloromethane solution on a sodium
REFERENCES AND NOTES
-1
chloride plate): ν 3335 (NH), 1686 (C=O) 1256, 1124 (CO) cm ;
1
H nmr (deuteriochloroform): δ 2.39 (s, 3H), 3.85-3.88 (m, 2H),
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