Synthesis of lariat ether carboxylic acids based on dibenzo- 16-crown-5

Article abstract of DOI:10.1002/jhet.5570380201

Synthetic routes to forty-seven dibenzo-16-crown-5 compounds with pendant carboxylic acid groups are reported. When taken together with previously described lariat ether carboxylic acids, these new compounds provide several series with systematic structur

Full text of DOI:10.1002/jhet.5570380201

Mar-Apr 2001
Synthesis of Lariat Ether Carboxylic Acids
Based on Dibenzo-16-crown-5
311
Richard A. Bartsch*, Charles L. Cowey, Sadik Elshani*, Mi-Ja Goo,
Vincent J. Huber, Sheryl N. Ivy, Russell J. Johnson, Jong Seung Kim, Elzbieta Luboch,
Joseph A. McDonough, Michael J. Pugia, Byungki Son and Qiang Zhao
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061
Received September 25, 2000
Synthetic routes to forty-seven dibenzo-16-crown-5 compounds with pendant carboxylic acid groups are
reported. When taken together with previously described lariat ether carboxylic acids, these new compounds
provide several series with systematic structural variations including changes in the identity and attachment
site(s) of one or more lipophilic groups and the length of the spacer that connects the carboxylic acid group
to the polyether framework.
Journal of Heterocyclic Chem., 38, 311 (2001).
Introduction.
Previously we have described the preparation of several
dibenzo-16-crown-5 carboxylic acids [7,9,11,13,
14,19,26,32-34]. However, these compounds provide only
limited structural variation. We now report synthetic
strategies for the preparation of 47 new dibenzo-16-
crown-5 carboxylic acids. In combination with the
reported compounds, these proton-ionizable lariat ethers
provide systematic variations of several structural features.
Synthetic macrocyclic polyether ligands (crown ethers)
have been used widely for the complexation and selective
extraction of a variety of metal ion species [1]. In such
systems, the counteranion plays an important role in
determining the extraction efficiency and selectivity [2]. The
potential of crown ethers as the next generation of specific
extracting agents for metal ions was markedly enhanced by
the introduction of crown ethers which bear pendant acidic
functions [3]. An important advantage of such proton-ioniz-
able lariat ethers is that the ionized group on the side arm
provides the counteranion necessary for transport of a metal
ion into an organic layer during separation by solvent extrac-
tion or transport across liquid membranes. This factor is of
immense importance to potential practical applications in
which hard aqueous phase anions of chloride, nitrate, and
sulfate would be involved [4].
Results and Discussion.
Structures, physical properties, nmr and ir spectral
data and elemental analyses data for the new
compounds are given in Tables 1-8. In several instances,
previously reported compounds are included for
comparison. For the preparation of the new lariat ether
carboxylic acids, several different synthetic strategies
were utilized which will be discussed for each family of
compounds.
For several years, we have been involved in the design
and preparation of lariat ether carboxylic acids and the
study of their behavior in metal ion separation processes
[4-20]. These ligands have been found to be effective
chelating agents for alkali and alkaline earth metal cations
and trivalent lanthanide ions [4-25]. In addition to their use
as metal ion complexing agents, lariat ether carboxylic
acids are important starting materials for the synthesis of
lariat ethers with pendant alcohol [26,27], amide [26,28],
ester [29], hydroxamate [19,21], and N-(X)sulfonyl
carboxamide [30,31] groups, as well as bis(crown ether)s
and macrotricyclic polyether compounds [26].
Synthesis of sym-(R)dibenzo-16-crown-5-oxyacetic Acids.
As shown in Scheme 1, sym-hydroxydibenzo-16-crown-5
(82) [35] was reacted with sodium hydride and the
appropriate 2-bromocarboxylic acid in tetrahydrofuran to
rovide dibenzo-16-crown-5 lariat ether carboxylic acids 1-8
in which a linear alkyl group is incorporated in the side arm
alpha to the carboxylic acid group (Table 1). Attachment of a
lipophilic alkyl group was found to reduce loss of ionized
sym-dibenzo-16-crown-5-oxyacetic acid from a chloroform
solution into a contacting aqueous solution during competi-
tive solvent extraction of alkali metal cations [5].

312
Vol. 38
R. A. Bartsch, C. L. Cowey, S. Elshani, M.-J. Goo, V. J. Huber, S. N. Ivy,
R. J. Johnson, J. S. Kim, E. Luboch, J. A. McDonough, M. J. Pugia, B. Son and Q. Zhao
Table 1
Data for Lariat Ether Carboxylic Acids 1-11
Analysis %
Calcd./Found
1
Compound R (Ar) R'(Ar') Method Yield
Mp
(°C)
H NMR (deuteriochloroform)
IR
(cm )[b]
Molecular
Formula
-1
[a]
(%)
δ (ppm)
C
H
1
2
3
4
H
H
H
H
C H
A
A
A
A
B
B
B
B
B
B
A
40[c]
40[c]
23[c]
27[c]
85[d]
80[e]
66[e]
70[e]
90[d]
64[e]
48
2
5
9
C H
4
C H
6
13
17
C H
8
5
6
7
H
H
H
C
C
C
H
10 21
H
12 25
H
14 29
8
9
H
CH
C
H
16 33
C H
95-96
0.70-1.90 (m, 20H),
3.50-4.30 (m, 13H)
3390-3200
(COOH)
C H O •
30 42 8
62.14 7.38
62.39 7.41
3
8
17
0.75CH Cl
2 2
6.90 (s, 8H), 8.20 (br s, 1H)
1706 (C=O)
10
11
C H
C H
B
B
97[d]
86[d]
6
5
6
5
5
C
H
C H
10 21
6
[a] See Scheme 2; [b] Deposit from dichloromethane solution on a sodium chloride plate; [c] Reference 7; [d] Later preparation; [e] Reference 19.
Lariat ether carboxylic acids 12-58 (Tables 2-4) with an
alkyl, branched alkyl, cycloalkyl, fluoroalkyl, aryl, aralkyl,
alkenyl and alkynyl group attached to the polyether ring
carbon geminal to an oxyacetic acid side arm were prepared
by reaction of the corresponding lariat ether alcohol with
sodium or potassium hydride in tetrahydrofuran followed
by addition of bromoacetic acid. Lariat ether carboxylic
acids 9-11 (Table 1) with lipophilic groups at both the
geminal position and on the side arm were prepared by
reaction of the appropriate lariat ether alcohol and sodium
or potassium hydride in tetrahydrofuran and the appropriate
2-bromocarboxylic acid as shown in Scheme 2. The sym-
(R)(hydroxy)dibenzo-16-crown-5 precursors were
prepared by reaction of [9] and the appropriate Grignard
reagent [9,19,21,27]. In addition to reducing ligand loss
from the organic phase during extraction of metal ions from
aqueous solutions, the geminal substituent preorganizes the
metal ion binding site by orienting the carboxylic acid
group over the crown ether cavity [36].
method (Scheme 4), nitro and sulfonic acid groups were
introduced into the benzene rings of the pre-formed lariat
ether carboxylic acids by nitration [33] and sulfonation
[11], respectively. Nitration of sym-dibenzo-16-crown-5-
oxyacetic acid (12) and sym-(propyl)dibenzo-16-crown-5-
oxyacetic acid (15) was conducted with nitric acid in
acetic acid-chloroform at room temperature to give
dinitrated lariat ether carboxylic acids 60 and 64,
respectively, in very high yields. Under these mild
conditions [37], clean dinitration occurred. With only
acetic as the solvent, over-nitration might take place [38].
In 60 and 64, structural isomers of the dinitrated products
are possible due to the four potential nitration positions in
each aromatic ring of the dibenzocrown ether carboxylic
acids. Multiple spots were observed for both dinitrated
products 60 and 64 when analyzed by thin layer
chromatography. Broad melting point ranges indicate the
presence of isomeric mixtures in dinitrated lariat ether
carboxylic acids 60 and 64.
Dibenzo-16-crown-5 lariat ether carboxylic acids with
substituents on both benzene rings (Table 5) were prepared
by two methods. In the first method (Scheme 3), the
appropriate lariat ether alcohol containing the ring
substituents [27,32] was reacted with sodium hydride in
tetrahydrofuran and then bromoacetic acid to give the
lariat ether carboxylic acids 59, 63 and 67. In the second
Reduction of di(nitrobenzo)-18-crown-6 to the
corresponding diamine was reported by catalytic
hydrogenation in N,N-dimethylformamide (DMF) or
N,N-dimethylacetamide [33,37]. However, catalytic
hydrogenation (Pd/C catalyst, 50 psi of hydrogen) of the
dinitrated lariat ether carboxylic acid 60 in N,N-dimethyl-
formamide, 2-methoxyethanol, or ethanol produced

313
Synthesis of Lariat Ether Carboxylic Acids Based on Dibenzo-16-crown-5
Mar-Apr 2001
Table 2
Data for Lariat Ether Carboxylic Acids 12-37
Analysis
Calcd./Found
1
Compound
Method
[a]
Yield
(%)
Mp
(°C)
H NMR (deuteriochloroform)
IR
(cm )[b]
Molecular
Formula
-1
R
H
δ (ppm)
C
H
12
A
A
C
C
C
A
C
C
82[c]
84[d]
92[e]
69[d]
91[e]
62
13
14
15
16
CH
3
C H
2
5
7
C H
3
93[f]
88
CH(CH )
124-125
116-118
155-157
138-139
1.17 (s, 6H), 2.63-2.68 (m, 1H),
3.81-4.18 (m, 10H), 4.81-4.86
(d, 2H, J = 10Hz), 4.88 (s, 2H),
6.80-6.90 (m, 8H)
3.63-4.40 (m, 10H), 4.63-4.68
(d, 2H, J = 10Hz), 5.07 (s, 2H),
6.69-7.02 (m, 8H), 8.50 (br s, 1H)
3350 (COOH)
1743 (C=O)
C
H O
24 30 8
64.56 6.77
64.35 6.77
3 2
17
C F
A
71
3358 (COOH)
1748 (C=O)
C H F O
24 23 7 8
50.36 4.05
50.62 4.19
3
7
18
19
C H
A
A
55[g]
79
4
9
C H
0.80-2.20 (m, 11H), 3.75-4.35
(m, 10H), 4.63-4.68 (d, 2H,
J = 10Hz), 4.85 (s, 2H),
6.69-7.00 (m, 8H)
1.15 (s, 9H), 2.05 (s, 2H),
3.86-4.13 (m, 10H, 4.63-4.68
(d, 2H, J = 10Hz), 4.87 (s, 2H),
6.80-6.97 (m, 8H)
3361 (COOH)
1752 (C=O)
C
H
O
O
65.81 7.22
65.96 7.32
5
11
26 34
8
20
CH C(CH )
C
76
3384 (COOH)
1734 (C=O)
C H
26 34
65.81 7.22
66.17 7.06
2
3 3
8
21
22
c-C H
B
A
C
C
A
26[h]
88[d]
85
93[e]
90
6
11
C H
6
13
23
24
C F
115-117
102-103
3.65-4.42 (m, 10H), 4.61-4.66
(d, 2H, J = 10Hz), 5.09 (s, 2H),
6.89-7.04 (m, 8H)
0.89-0.94 (t, 3H, J = 6Hz),
1.33 (s, 10H),1.93-1.98 (q, 2H,
J = 6Hz), 3.82-3.99 (m, 4H),
4.02-4.17 (m, 6H), 4.58-4.61
(d, 2H, J = 9Hz), 4.85 (s, 2H),
6.81-6.99 (m, 8H)
3356 (COOH)
1750 (C=O)
C H F O
27 23 13 8
44.89 3.21
44.42 3.41
6
13
C H
A
B
79
76
3358 (COOH)
1771 (C=O)
C H O
28 38 8
66.91 7.62
66.85 7.66
7
15
C
77
25
26
C H
A
C
A
90[g]
95[e]
87
8
17
C F
58-60
oil
3.68-4.45 (m, 10H), 4.68-4.73
(d, 2H, J = 10Hz), 5.10 (s, 2H),
6.85-7.03 (m, 8H)
0.89-1.02 (m, 6H), 1.27-1.68
(m, 9H),1.88-2.01 (m, 2H),
3.83-4.18 (m, 10H), 4.53-4.58
(dd, 2H, J = 10, 2 Hz), 4.88
(s, 2H), 6.82-7.00 (m, 8H)
3360 (COOH) C
1751 (C=O)
H
H O
F
O • 41.48 2.91
8
17
29 23 17
8
41.48 3.06
2
27
CH CH(C H )-
C
58
3366 (COOH)
1772, 1774 (C=O) 0.25C H
C H O • 68.00 8.11
29 40 8
2
2
5
(CH ) CH
67.99 8.03
2 3
3
6 14

314
Vol. 38
R. A. Bartsch, C. L. Cowey, S. Elshani, M.-J. Goo, V. J. Huber, S. N. Ivy,
R. J. Johnson, J. S. Kim, E. Luboch, J. A. McDonough, M. J. Pugia, B. Son and Q. Zhao
Table 2 (continued)
Data for Lariat Ether Carboxylic Acids 12-37
Analysis
Calcd./Found
1
Compound
Method
[a]
Yield
(%)
Mp
(°C)
H NMR (deuteriochloroform)
IR
(cm )[b]
Molecular
Formula
-1
R
δ (ppm)
C
H
28
C H
B
C
98
82
98-99
0.87-0.92 (t, 3H, J = 6Hz),
1.30-1.43 (m, 14H), 1.93-1.96
(m, 2H), 3.82-3.91 (m, 4H),
4.02-4.18 (m, 6H), 4.58-4.61
(d, 2H, J = 9Hz), 4.85
3364 (COOH)
1748 (C=O)
C
H
O
67.90 7.98
68.06 8.01
9
19
30 42
8
(s, 2H), 6.81-7.00 (m, 8H)
29
30
C
C
H
A
B
C
C
57[i]
78[h]
93[e]
78
10 21
H
109-111
104-105
99-101
0.85-0.91 (t, 3H, J = 6Hz),
1.15-1.30 (m, 18H), 1.89-1.95
(m, 2H), 3.80-4.10 (m, 10H,
4.50-4.55 (d, 2H, J = 10Hz), 4.80
(s, 2H), 6.85-7.00 (m, 8H)
0.85-0.91 (t, 3H, J = 6Hz),
1.20-1.30 (m, 20H), 3.70-4.30
(m, 10H), 4.50-4.55 (d, 2H,
J = 10Hz), 4.85 (s, 2H),
3368 (COOH)
1771 (C=O))
C
C
C
H
O
O
O
68.79 8.30
68.83 8.45
11 23
32 46
8
8
8
31
32
C
C
H
A
C
92
76
3363 (COOH)
1770 (C=O)
H
33 48
69.20 8.45
68.63 8.54
12 25
6.89-7.05 (m, 8H)
H
C
55
0.85-0.91 (t, 3H, J = 6Hz),
1.25 (s, 22H), 1.92-2.04 (m, 2H),
3.80-4.21 (m, 10H), 4.56-4.61
(d, 2H, J = 10Hz), 4.84 (s, 2H),
6.79-7.00 (m, 8H)
3356 (COOH)
H
34 50
69.60 8.53
13 27
1769 (C=O) 69.38 8.57
33
34
C
C
H
A
A
72[g]
81
14 29
H
98-100
0.84-0.90 (t, 3H, J = 6Hz),
1.21 (s, 26H), 1.92-2.01
3367 (COOH)
1772 (C=O)
C
C
H
O
70.33 8.85
70.26 9.17
15 31
36 54
8
8
(m, 2H), 3.70-4.20 (m, 10H),
4.52-4.57 (d, 2H, J = 10Hz),
4.77 (s, 2H), 6.72-7.04 (m, 8H)
0.85-0.91 (t, 3H, J = 6Hz),
1.22-1.38 (m, 28H), 1.92-2.01
(m, 2H), 3.70-4.27 (m, 10H),
4.52-4.57 (d, 2H, J = 10Hz),
4.80 (s, 2H), 6.85-7.09 (m, 8H)
35
C
H
A
C
85
54
101-103
3369 (COOH)
1771 (C=O)
H
37 56
O
70.67 8.98
70.25 9.03
16 33
36
37
C
C
H
A
B
A
84
89[h]
92
18 37
H
102-104
0.83-0.88 (t, 3H, J = 6Hz),
3370 (COOH)
C
H
O
71.89 9.42
72.01 9.43
20 41
41 64
8
1.20 (s, 36H), 1.95-2.13 (m, 2H), 1771 (C=O)
3.60-4.20 (m, 10H), 4.53-4.58
(d, 2H, J = 10Hz), 4.82 (s, 2H),
6.87-7.11 (m, 8H)
[a] See Scheme 2; [b] Deposit from dichloromethane solution on a sodium chloride plate; [c] Reference 7; [d] Reference 16; [e] Reference 34;
[f] Reference 14; [g] Reference 9; [h] Reference 19; [i] Reference 13.
dark-colored products which could not be purified by
recrystallization, sublimation or column chromatography.
Acetylation of the crude product also failed to provide
material that could be purified. Subsequently, it was found
that 85% hydrazine hydrate in ethanol reduced 60 to the
corresponding diamine 61 in good yield.
Compared with sym-(R)dibenzo-16-crown-5-oxyacetic
acids, lariat ether carboxylic acids 68-73 (Table 6) have
one to three additional methylene groups in the spacer. For
the preparation of lariat ether carboxylic acids 68-72, two
methods were employed. In the first synthetic route
(Scheme 5), potassium tert-butoxide-catalyzed
cyanoethylation of the corresponding lariat ether
secondary alcohols 82 and 83 in neat acrylonitrile (for 82)
or acrylonitrile in tetrahydrofuran (for 83) gave the
corresponding lariat ether nitriles 84 and 85 in 63 and 48%
yields, respectively. Attempted cyanoethylation of lariat
ether alcohol 83 in neat acrylonitrile gave a complex
Synthesis of Lariat Ether 3-Oxypropanoic, 4-Oxybutanoic
and 5-Oxypentanoic Acids.
The length of the spacer that connects the acidic
function to the polyether ring is an important structural
parameter for proton-ionizable lariat ethers [39].

315
Synthesis of Lariat Ether Carboxylic Acids Based on Dibenzo-16-crown-5
Mar-Apr 2001
Table 3
Data for Lariat Ether Carboxylic Acids 38-50
Analysis %
Calcd./Found
1
Compound
R
Method
[a]
Yield
(%)
Mp
(°C)
H NMR (deuteriochloroform)
IR
(cm )[b]
Molecular
Formula
-1
δ (ppm)
C
H
38
CH CH C H
C
75
154-155 2.03-2.34 (m, 2H), 2.81-2.90
(m, 2H), 3.80-4.38 (m, 10H),
3356 (COOH)
1768 (C=O)
C
H
O
68.50
68.23
6.34
6.40
2
2
6
5
29 32
8
4.59-4.64 (d, 2H, J = 10Hz),
4.94 (s, 2H), 6.47-7.07 (m, 8H),
7.27-7.37 (m, 5H), 9.76 (br s, 1H)
135-136 1.78-1.89 (m, 2H), 1.94-2.05
(m, 2H), 2.70-2.77 (t, 2H,
39
40
(CH ) C H
C
68
3357 (COOH)
1768 (C=O)
C
H
30 34
O
68.96
68.57
6.56
6.63
2 3
6
5
8
J = 7Hz), 3.76-4.28 (m, 10H),
4.47-4.52 (d, 2H, J = 10Hz),
4.83 (s, 2H), 6.78-7.00 (m, 8H),
7.19-7.36 (m, 5H), 9.91 (br s, 1H)
(CH ) C H
C
C
53
63
85-86
1.52-1.59 (m, 2H), 1.69-1.84
(m, 2H), 1.94-2.02 (m, 2H),
2.67-2.74 (t, 2H, J = 8Hz),
3.79-4.23 (m, 10H), 4.54-4.59
(d, 2H, J = 10Hz), 4.84 (s, 2H),
6.79-7.00 (m, 8H), 7.16-7.34
(m, 5H), 9.95 (br s, 1H)
3354 (COOH)
1769 (C=O)
C
C
H
O
69.39
69.57
6.76
6.70
2 4
6
5
31 36
8
41
(CH ) C H
104-105 1.45-1.49 (m, 4H), 1.67-1.74
(m, 2H), 1.91-2.03 (m, 2H),
2.62-2.69 (t, 2H, J = 6Hz),
3355 (COOH)
1770 (C=O)
H
O
69.81
69.97
6.96
6.81
2 5
6
5
32 38
8
3.78-4.19 (m, 10H), 4.53-4.58
(d, 2H, J = 10Hz), 4.88 (s, 2H),
6.78-6.99 (m, 8H), 7.14-7.32
(m, 5H), 9.89 (br s, 1H)
42
43
C H
B
B
76[c]
67
6
5
2-(CH )C H
122-124 2.59 (s, 3H), 3.85-3.90 (m, 2H),
4.03-4.19 (m, 6H), 4.51-4.55
(d, 2H, J = 8Hz), 4.80-4.83
3656-2900
(COOH),
1734 (C=O)
C
C
C
H
O
O
O
68.00
67.61
6.11
6.28
3
6
4
4
4
4
28 30
8
8
8
(d, 2H, J = 6Hz), 4.84 (s, 2H),
6.78-6.98 (m, 8H), 7.27-7.32
(m, 3H), 7.67-7.70 (m, 1H)
44
45
46
3-(CH )C H
B
B
B
87
82
161-163 2.44 (s, 3H), 3.85-3.90 (m, 2H),
4.05-4.19 (m, 6H), 4.26-4.30
(d, 2H, J = 8Hz), 4.79-4.82
3628-2900
(COOH),
1731 (C=O)
H
28 30
68.00
68.40
6.11
6.33
3
6
(d, 2H, J = 6Hz), 4.92 (s, 2H),
6.71-6.98 (m, 8H), 7.20-7.34
(m, 1H), 7.37-7.45 (m, 3H)
4-(CH )C H
179-180 2.40 (s, 3H), 3.85-3.90 (m, 2H),
4.02-4.15 (m, 6H), 4.28-4.31
(d, 2H, J = 6Hz), 4.74-4.77
3645-2900
(COOH),
1734 (C=O)
H
28 30
68.00
67.84
6.11
6.32
3
6
(d, 2H, J = 6Hz), 4.88 (s, 2H),
6.72-6.98 (m, 8H), 7.24-7.29
(m, 2H), 7.52-7.55 (d, 2H, J = 6Hz)
3-(CF )C H
89[d]
90
3
6
47 4-(CH =CH)C H
C
178-179 3.91-4.20 (m, 8H), 4.27-4.32
(d, 2H, J = 10Hz), 4.77-4.83
(d, 2H, J = 10.6Hz), 4.91 (s, 2H),
5.35 (s, 1H) 5.78 (s, 1H),
3430 (COOH)
1735 (C=O)
C
H
O
68.76
68.52
5.97
5.98
2
6
4
29 30
8
5.87 (s, 1H),6.70-6.96 (m, 8H),
7.50-7.63 (m, 4H)

316
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R. A. Bartsch, C. L. Cowey, S. Elshani, M.-J. Goo, V. J. Huber, S. N. Ivy,
R. J. Johnson, J. S. Kim, E. Luboch, J. A. McDonough, M. J. Pugia, B. Son and Q. Zhao
Table 3 (continued)
Data for Lariat Ether Carboxylic Acids 38-50
Analysis %
Calcd./Found
1
Compound
R
Method
[a]
Yield
(%)
Mp
(°C)
H NMR (deuteriochloroform)
IR
Molecular
Formula
-1
δ (ppm)
(cm )[b]
C
H
48
4-[CH =C(CH )]-
A
80
195-196 2.17 (s, 3H), 3.99-4.18 (m, 8H),
4.46-4.51 (d, 2H), J = 10Hz),
4.57-4.62 (d, 2H, J = 10Hz),
3425 (COOH)
1734 (C=O)
C H O •
30 32 8
68.74
68.73
6.23
6.23
2
3
C H
O.2H O
6
4
2
4.66 (s, 2H), 5.09 (s, 1H), 5.40
(s, 1H), 6.78-6.91 (m, 8H),
7.45-7.54 (t, 2H, J = 8Hz),
7.78-7.82 (d, 2H, J = 8Hz)
49
50
3,5-(CH ) C H
B
B
72
115-117 2.40 (s, 6H), 3.96-4.12 (m, 2H),
4.13-4.21 (m, 6H), 4.23-4.28
(d, 2H, J = 10Hz), 4.78-4.83
3650-2900
(COOH),
1734 (C=O)
C H O
29 32 8
71.98
72.08
6.71
6.70
3 2
6
3
(d, 2H, J = 10Hz), 4.92 (s, 2H),
6.70-6.96 (m, 9H), 7.26 (s, 2H)
3,5-(CF ) C H
6 3
96[d]
3 2
[a] See Scheme 2; [b] Deposit from dichloromethane solution on a sodium chloride plate; [c] Reference 19; [d] Reference 21.

317
Synthesis of Lariat Ether Carboxylic Acids Based on Dibenzo-16-crown-5
Mar-Apr 2001
Table 4
Data for Lariat Ether Carboxylic Acids 51-58
Analysis %
Calcd./Found
1
Compound
R
Method
[a]
Yield
(%)
Mp
(°C)
H NMR (deuteriochloroform)
IR
(cm )[b]
Molecular
Formula
-1
δ (ppm)
C
H
51
CH=C(CH )
C
A
A
C
92
92
97
94
65-67
87-89
oil
1.94-1.97 (d, 6H, J = 6Hz),
3.84-4.17 (m, 10H), 4.50-4.55
(d, 2H, J = 10Hz), 4.66 (s, 2H),
5.43-5.65 (m, 1H), 6.81-6.96
(m, 8H)
1.30-2.02 (m, 12H), 3.90-4.26
(m, 10H), 4.56-4.62 (d, 2H,
J = 12Hz), 4.87 (s, 2H),4.91-5.03
(m, 2H), 5.72-5.91 (m, 1H),
6.87-7.01 (m, 8H)
1.32-2.05 (m, 16H), 3.90-4.26
(m, 10H), 4.56-4.62 (d, 2H,
J = 12Hz), 4.85 (s, 2H), 4.90-5.04
(m, 2H), 5.70-5.90 (m, 1H),
6.89-7.00 (m, 8H)
0.90-0.96 (t, 3H, J = 7.1Hz),
1.32-1.64 (m, 4H), 2.26-2.32
(t, 2H, J = 6.9Hz), 3.81-4.05
(m, 4H), 4.09-4.26 (m, 6H), 4.48
(s, 2H), 4.52-4.57 (d, 2H,
J = 10Hz), 6.78-7.08 (m, 8H)
3384 (COOH)
1770 (C=O)
C
H O •
25 30 8
64.47
64.55
6.67
6.84
3 2
0.4H O
2
52
53
54
(CH ) CH=CH
3357 (COOH)
1744 (C=O)
C
H
O
O
O
67.68
67.80
7.44
7.49
2 6
2
29 38
8
8
8
(CH ) CH=CH
3357 (COOH)
1746 (C=O)
C
C
H
68.61
68.51
7.80
7.51
2 8
2
31 42
C≡C(CH ) CH
66-67
3700-2300
(COOH),
2241 (C≡C),
1741 (C=O)
H
66.93
66.91
6.66
6.72
2 3
3
3
3
3
27 32
55
56
57
58
C≡C(CH ) CH
C
C
C
C
85
84
88
86
103-105 0.85-0.91 (t, 3H, J = 6Hz),
1.18-1.66 (m, 8H), 2.25-2.31
(t, 2H, J = 7Hz), 3.82-4.05
(m, 4H), 4.08-4.27 (m, 6H),
4.48 (s, 2H), 4.52-4.57 (d, 2H,
J = 10Hz), 6.79-7.08 (m, 8H)
105-106 0.87-0.93 (t, 3H, J = 6Hz),
1.14-1.67 (m, 12H), 2.25-2.31
(t, 2H, J = 7Hz), 3.80-4.05
3700-2300
(COOH),
2241 (C≡C),
1745 (C=O)
C
C
C
C
H
O
O
O
O
67.95
67.71
7.08
6.92
2 5
29 36
8
8
8
8
C≡C(CH ) CH
3700-2300
(COOH)
2241 (C≡C)
1741 (C=O)
H
68.87
68.94
7.46
7.23
2 7
31 40
(m, 4H), 4.08-4.28 (m, 6H),
4.48 (s, 2H), 4.52-4.57 (d, 2H,
J = 10Hz), 6.78-7.10 (m, 8H)
0.87-0.93 (t, 3H, J = 6Hz),
1.17-1.66 (m, 16H), 2.25-2.31
(t, 2H, J = 7Hz), 3.81-4.05
(m, 4H), 4.08-4.27 (m, 6H), 4.48
(s, 2H), 4.52-4.57 (d, 2H,
J = 10Hz), 6.79-7.08 (m, 8H)
0.88-0.94 (t, 3H, J = 6Hz),
1.16-1.66 (m, 20H), 2.25-2.31
(t, 2H, J = 7Hz), 3.80-4.05
(m, 4H), 4.08-4.29 (m, 6H), 4.48
(s, 2H), 4.51-4.56 (d, 2H, J = 10Hz),
6.78-7.09 (m, 8H)
C≡C(CH ) CH
90-91
88-90
3700-2300
(COOH)
2243 (C≡C)
1742 (C=O)
H
69.69
69.75
7.80
7.81
2 9
33 44
C≡C(CH ) CH
3700-2300
(COOH)
2241 (C≡C)
1741 (C=O)
H
70.45
70.52
8.11
8.27
2 11
3
35 48
[a] See Scheme 2; [b] Deposit from dichloromethane solution on a sodium chloride plate.

318
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R. A. Bartsch, C. L. Cowey, S. Elshani, M.-J. Goo, V. J. Huber, S. N. Ivy,
R. J. Johnson, J. S. Kim, E. Luboch, J. A. McDonough, M. J. Pugia, B. Son and Q. Zhao

319
Synthesis of Lariat Ether Carboxylic Acids Based on Dibenzo-16-crown-5
Mar-Apr 2001
mixture of oligomers. Hydrolysis of 84 and 85 was
performed by bubbling hydrochloric acid gas through a
refluxing methanol solution of the lariat ether nitrile to
give lariat ether methyl esters 86 and 87 in 94 and 74%
yields, respectively. Saponification with potassium
hydroxide in 95% ethanol gave the lariat ether
oxypropanoic acids 68 and 69 in 65 and 90% yields,
respectively.
Lariat ether esters 86 and 87 showed a pronounced
tendency to undergo a retro Michael addition (Scheme 6,
path b) during hydrolysis, if the ester group was not
cleaved quickly (Scheme 6, path a). Therefore, methyl
esters were favored over ethyl esters in this synthetic route.
The preparation of lariat ether carboxylic acid 68 was
reported previously [7] by another method, but in low
overall yield.
The hydrolysis of methyl ester 87 and the corresponding
ethyl ester was investigated using several reaction
conditions (Table 9). The hydrolyses were conducted at
room temperature using varying amounts of potassium
hydroxide as the base in 95% ethanol and in dioxane. In
addition to the desired lariat ether carboxylic acid 69, the
retro Michael adduct 83 (15%) and some recovered
reactant were obtained when four equivalents of potassium
hydroxide were used to hydrolyze the ethyl ester in 95%
ethanol (Entry 1). With eight equivalents of potassium
hydroxide in 95% ethanol, a 91% yield of lariat ether
carboxylic acid 69 was obtained (Entry 2). With 10
equivalents of potassium hydroxide in dioxane, the amount
of retro Michael decomposition increased relative to the
desired hydrolysis product (Entries 3 and 4). When the
more labile methyl ester 87 (Entry 5) was reacted with
eight equivalents of potassium hydroxide in 95% ethanol,
lariat ether carboxylic acid 69 was obtained in 90% yield.
For lariat ether carboxylic acids 70-72 (Table 6), a
somewhat different approach was utilized (Scheme 7).
Reaction of lariat ether alcohols 88-90 with methanesulfonyl
chloride in dichloromethane in the presence of triethylamine
provided lariat ether mesylates 91-93, respectively, in
90-94% yields. The lariat ether mesylates 91 and 92 were
reacted with sodium cyanide in dimethyl sulfoxide at 45° (at
90° for 98) to give the lariat ether nitriles 94-96, respectively,
in 60-84% yields. The progress of these reactions were

320
Vol. 38
R. A. Bartsch, C. L. Cowey, S. Elshani, M.-J. Goo, V. J. Huber, S. N. Ivy,
R. J. Johnson, J. S. Kim, E. Luboch, J. A. McDonough, M. J. Pugia, B. Son and Q. Zhao

321
Synthesis of Lariat Ether Carboxylic Acids Based on Dibenzo-16-crown-5
Mar-Apr 2001
methyl esters 97-99 were obtained in 42-79% yields,
respectively. Hydrolysis with potassium hydroxide in 95%
ethanol at room temperature gave the lariat ether carboxylic
acids 70-72, respectively, in high yields (88-97%).
Synthesis of Lariat Ether Acetic, 3-Propanoic and 4-(2-
Oxabutanoic Acid)s.
For the dibenzo-16-crown-5 carboxylic acids described
above, an oxygen atom connects the side arm to the
polyether ring. In contrast, for lariat ether carboxylic acids
74-77 (Table 7) a carbon atom connects the side arm to the
dibenzo-16-crown-5 unit.
The synthesis of hydroxymethyl lariat ethers 104 and
105 which are precursors to lariat ether carboxylic acids
79, 81 and 82 is shown in Scheme 9. Vinylidine dibenzo-
crown ethers 102 and 103 were prepared by cyclization of
bisphenols 100 and 101 with methallyl dichloride and
cesium carbonate in acetonitrile to give the desired
products in 72-74% yields. Hydroboration-oxidation of
102 and 103 with borane-tetrahydrofuran complex, fol-
lowed by oxidation with hydrogen peroxide and basic
hydrolysis gave lariat ether alcohols 104 and 105 in 60 and
45% yields, respectively.
conveniently monitored by thin layer chromatography. When
the preparation of 94 was attempted in dimethyl sulfoxide at
90°, the primary product was a 57% yield of sym-
(hydroxy)(methyl)dibenzo-16-crown-5. This decomposition
product is proposed to result from the retro Michael-type
elimination shown in Scheme 8. For hydrolysis, lariat ether
nitriles 94-96 were refluxed in anhydrous methanol and
anhydrous hydrochloric acid gas was bubbled through the
solution for 50 hours. After quenching with water, lariat ether
(sym-Dibenzo-16-crown-5)acetic acid (74) was synthe-
sized as shown in Scheme 10. Reaction of lariat ether
alcohol 104 with methanesulfonyl chloride in
dichloromethane in the presence of triethylamine gave lar-
iat ether mesylate 106, which was treated with sodium
cyanide in dimethyl sulfoxide at 60° to provide a 98%
yield of lariat ether nitrile 107. Passing hydrogen chloride
gas through a refluxing methanolic solution of 107 for 16
hours gave a quantitive yield of lariat ether methyl ester

322
Vol. 38
R. A. Bartsch, C. L. Cowey, S. Elshani, M.-J. Goo, V. J. Huber, S. N. Ivy,
R. J. Johnson, J. S. Kim, E. Luboch, J. A. McDonough, M. J. Pugia, B. Son and Q. Zhao
Table 5
Data for Lariat Ether Carboxylic Acids 59-67
Analysis %
Calcd./Found
1
Compound
R
R'
Method Yield
Mp
(°C)
H NMR (deuteriochloroform)
IR
(cm )[b]
Molecular
Formula
-1
[a]
(%)
δ (ppm)
C
H
59
60
61
H
H
H
C(CH )
A
86[c]
99[d]
89
3 3
NO
NH
2
2
179-180
3.20-4.50 (m, 15H), 4.50-4.52
(br s, 4H), 5.80-7.00 (m, 6H),
8.80-9.20 (br s, 1H) [e]
3370, 3290,
3180 (COOH,
C
H
0.3H 0
N O • 57.34
6.10
6.21
21 26
2 8
57.42
2
NH ), 1680
2
(C=O) [f]
62
63
H
CH
SO H
93[e]
74
3
C(CH )
A
97-99
83-89
0.80-1.30 (m, 21H), 3.40-4.30
(m, 12H) 4.75 (s, 2H), 6.80-7.00
(m, 6H), 8.90 (br s, 1H)
1.00-1.20 (m, 3H), 1.40-1.70
(m, 2H), 1.85-2.10 (m, 2H),
3.80-4.90 (m, 14H), 6.80-7.05
(m, 2H), 7.65-8.10 (m, 4H)
3550 (COOH)
1715 (C=O)
C H O • 63.59
30 42 8
8.13
7.72
3
3 3
2.0H O
63.41
C H N O 53.73
24 28 2 12
2
64
C H
NO
99
3412 (COOH)
1735 (C=O)
5.26
5.27
3
7
2
53.54
65
66
67
CH
SO H
86[e]
82(e)
49[h]
3
3
C H
SO H
4
9
3
H
F
B
[a] See Scheme 2.; [b] Deposit from dichloromethane solution onto a sodium chloride plate.; [c] Reference 32; [d] Reference 33; [e]Reference 11;
[f] Dimethyl sulfoxide d-6; [g] Potassium bromide pellet; [h] Reference 21.
108. Hydrolysis with potassium hydroxide in 95% ethanol
at room temperature gave a quantitative yield of lariat
ether carboxylic acid 74.
The synthetic route to 3-(sym-dibenzo-16-crown-5)-
propanoic acid (75) is shown in Scheme 11. Lariat ether
alcohol 82 was converted into tosylate 109 in 97% yield.
This tosylate was reacted with 10 equivalents of lithium
bromide in hexamethylphosphoramide to give an 85%
yield of lariat ether bromide 110 which was photolyzed in
the presence of acrylic acid and tributyltin hydride [40] to
produce a 30% yield of the desired lariat ether carboxylic
acid 75.

323
Synthesis of Lariat Ether Carboxylic Acids Based on Dibenzo-16-crown-5
Mar-Apr 2001
Table 6
Data for Lariat Ether Carboxylic Acids 68-73
Analysis %
Calcd./Found
1
Compound
R
R'
n
Yield
(%)
Mp
(°C)
H NMR (deuteriochloroform)
IR
(cm )[b]
Molecular
Formula
-1
δ (ppm)
C
H
68
69
H
H
H
2
2
65, 6[b]
90
C(CH )
oil
1.27 (s, 18H), 2.71-2.82
(m, 2H), 3.80-4.51 (m, 15H),
6.67-7.12 (m, 6H)
1.52 (s, 3H), 2.65-2.71
(t, 2H, J = 6Hz),
3.91-4.36 (m, 14H),
6.60-6.99 (m, 8H)
1.90-1.98 (q, 2H, J = 6Hz),
2.54-3.00 (t, 2H, J = 6Hz),
3.65-4.50 (m, 15H), 6.80-7.00 1709 (C=O)
(m, 8H), 9.15 (br s, 1H)
1.49 (s, 3H), 1.87-1.92
(m, 2H), 2.47-2.53 (t, 2H,
J = 6Hz), 3.80-3.94 (m, 6H),
4.10-4.27 (m, 8H) 6.60-6.99
(m, 8H)
3700-2500
(COOH),
1728 (C=O)
3212 (COOH)
1719 (C=O)
C
H O •
30 42 8
63.92
64.01
7.56
7.73
3 3
0.5CH Cl
2
2
70
71
72
CH
H
H
H
2
3
3
88
97
92
161-162
C
C
C
H
O
O
O
63.88
63.55
6.47
6.20
3
23 28
8
H
oil
3600-2400
(COOH)
H
63.88
63.59
6.53
6.95
23 28
8
8
CH
128-129
3440 (COOH)
1707 (C=O)
H
24 30
64.56
64.34
6.77
6.60
3
73
H
H
4
72[b]
[a] Deposited from dichloromethane solution on a sodium chloride plate; [b] Reference 7.
The preparation of dibenzo-16-crown-5 compounds 76
and 77 with 4-(2-oxabutanoic acid) side arms is
summarized in Scheme 12. Reaction of hydroxymethyl
lariat ethers 104 and 105 with ethyl bromoacetate and
sodium hydride in tetrahydrofuran at room temperature
gave lariat ether esters 111 and 112 in 63 and 40% yields,
respectively. Hydrolysis with potassium hydroxide in 95%
ethanol provided lariat ether carboxylic acids 76 and 77 in
94% yields.
Synthesis of Lariat Ether Dicarboxylic Acids.
Dibenzo-16-crown-5 compounds 80 and 81 with two
carboxylic acid groups per molecule were prepared as
depicted in Scheme 13. Reduction of lariat ether nitriles 84
and 85 with borane-dimethylsulfide in tetrahydrofuran
gave lariat ether amines 113 and 114 in 54 and 40% yields,
respectively. Condensations of 113 and 114 with ethyl
bromoacetate and potassium carbonate in acetonitrile at
room temperature gave lariat ether diesters 115 and 116 in
Table 7
Data for Lariat Ether Carboxylic Acids 74-77
Analysis %
Calcd./Found
C
1
Compound
R
H
H
R'
H
H
X
Yield
(%)
Mp
(°C)
H NMR (deuteriochloroform)
IR
(cm )[a]
Molecular
Formula
-1
δ (ppm)
H
74
75
CO H
99
oil
2.87 (s, 3H), 3.70-4.00 (m, 4H),
4.05-4.35 (m, 8H), 6.69-7.09
(m, 8H)
1.41-2.04 (q, 2H, J = 6Hz),
2.35-2.44 (m, 1H), 2.66-2.72
(t, 2H, J = 6Hz), 3.91-
3400-2700
(COOH),
1709 (C=O)
3600-2400
(COOH),
C
H O •
62.31
62.53
6.03
6.06
2
21 24 7
0.25CH Cl
2
2
CH CO H
30 157-158
C H O •
22 26 7
0.1CDCl
64.05
64.00
6.35
6.22
2
2
3
1707 (C=O)
3.96 (m, 4H), 4.13-4.19
(m, 8H), 6.81-6.99 (m, 8H)
2.43-2.75 (m, 1H), 3.70-4.41
(m, 16H), 6.68-7.05 (m, 8H),
7.95 (br s, 1H)
1.27 (s, 18H), 2.51-2.81 (m, 1H), 3700-2400
3.69-4.44 (m, 16H),
6.68-7.07 (m, 6H)
76
77
H
H
H
OCH CO H 62 106-107
3700-2600
(COOH),
1738 (C=O)
C H O
22 26 8
63.15
63.28
6.26
6.41
2
2
C(CH )
OCH CO H 38
oil
C H O •
30 42 8
61.80
61.74
7.34
7.43
3 3
2
2
(COOH),
1740 (C=O)
0.8CH Cl
2 2
[a] Deposit from dichloromethane solution on a sodium chloride plate.

324
Vol. 38
R. A. Bartsch, C. L. Cowey, S. Elshani, M.-J. Goo, V. J. Huber, S. N. Ivy,
R. J. Johnson, J. S. Kim, E. Luboch, J. A. McDonough, M. J. Pugia, B. Son and Q. Zhao
Table 8
Data for Lariat Ether Carboxylic Acids 78-81
Analysis %
Calcd./Found
1
Compound
R
X
Yield
(%)
Mp
(°C)
H NMR (deuteriochloroform)
IR
(cm )[a]
Molecular
Formula
-1
δ (ppm)
C
H
78
79
80
H
H
H
OCH CO H
60[b]
2
2
OCH(C H )CO H 65[b]
6
5
2
CH N(CH CO H)
96
oil
oil
1.75-2.20 (m, 2H), 3.05-4.51
(m, 21H), 6.65-7.08 (m, 8H),
11.5 (br s, 2H)
3600-2400
(COOH),
1731,1633
(C=O)
C
C
H
NO
•
•
57.67
57.73
6.25
5.86
2
2
2
2
26 33
10
0.6HCl
81
C(CH ) CH N(CH CO H)
97
1.17 (s, 18H), 1.68-2.10 (m, 2H), 3700-2400
3.10-4.61 (m, 21H), 6.50-6.95
(m, 6H), 11.5 (br s, 2H)
H
NO
61.62
61.72
7.58
7.44
3 3
2
2
2
2
34 49
10
3
(COOH,
1739, 1606
(C=O)
0.3CDCl
[a] Deposited from dichloromethane solution onto a sodium chloride plate; [b] Reference 26.
Table 9
100 and 62% yields, respectively. Hydrolysis with
potassium hydroxide in 95% ethanol produced the lariat
ether dicarboxylic acids 80 and 81 in 97% yields.
Basic Hydrolysis of Lariat Ether Methyl Ester 87
and the Corresponding Ethyl Ester
Equivalents of
Time Yield of
Entry Ester Potassium Hydroxide Solvent
(hours) 69 (%)
EXPERIMENTAL
1
2
3
4
5
ethyl
ethyl
ethyl
ethyl
methyl
4
8
10
10
8
95% ethanol
95% ethanol
dioxane
dioxane
95% ethanol
2.50
1.75
0.50
0.25
0.25
57[a,b]
91
16[a]
32[b]
90
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. Pentane, hexane and hexanes were dried by distillation
from lithium aluminum hydride. Acetonitrile was dried over and
distilled from calcium hydride. Lariat ether alcohol 82 [35] and
bisphenols 100 [41] and 101 [32] were prepared by reported
methods.
[a] Decomposition product 82 was also observed; [b] Some unhydrolyzed
ester was present in the product mixture.
Melting points were determined with a Mel-Temp melting
point apparatus. Infrared (ir) spectra were recorded with a 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, AZ.
sulfate and evaporated in vacuo to give a crude product which
was chromatographed twice on silica gel with dichloromethane
and ethanol-dichloromethane (1:1) as the eluents to afford a
white crystalline solid. The yield and physical, spectral and
analysis data for 9 are given in Table 1.
General Procedure for the Preparation of sym-(Alkyl)-,
(Fluoroalkyl)- or (Alkenyl)dibenzo-16-crown-5-oxyacetic Acids
16, 17, 19, 20, 22-24, 26-28, 30-32 and 34-37.
Preparation of 2-[sym-(Methyl)dibenzo-16-crown-5-oxy]-
decanoic Acid (9).
Under nitrogen, 4.70 g (97 mmoles) of sodium hydride (50%
dispersion in mineral oil) was washed three times with pentane to
remove the mineral oil and was suspended in tetrahydrofuran
(50 ml). To the stirred mixture, 34 mmoles of sym-(methyl)-
hydroxydibenzo-16-crown-5 [27] in tetrahydrofuran (50 ml) was
added over a 1-hour period and the mixture was stirred for
2 hours. A solution of 7.16 g (28.5 mmoles) of 2-bromodecanoic
acid in tetrahydrofuran (50 ml) was added over a 10-hour period
and the mixture was stirred at room temperature for 48 hours.
The mixture was evaporated in vacuo and water (250 ml) was
added. The resultant basic aqueous solution was extracted with
hexane (3 x 100 ml) to remove the unreacted lariat ether alcohol.
The aqueous solution was acidified to pH 3 with 6 N hydrochloric
acid and extracted with dichloromethane (3 x 100 ml). The
combined dichloromethane extracts were dried over magnesium
Under nitrogen, sodium hydride (60 mmoles) or potassium
hydride (20 mmoles) was washed with hexanes to remove the
protecting mineral oil (when dry sodium hydride was used, this
step was omitted). The metal hydride was suspended in tetra-
hydrofuran (40 ml). To the stirred mixture, a solution of the lariat
ether alcohol (13 mmoles) [27] in tetrahydrofuran (100 ml) was
added dropwise over a 30-minute period and stirring was contin-
ued for 1 hour. To the mixture, 4.16 g (30 mmoles) of
bromoacetic acid in tetrahydrofuran (10 ml) was added dropwise
during a 1-hour period. The mixture was stirred at room tempera-
ture overnight and cooled to 0°. Water (20 ml) was added drop-
wise to destroy the unreacted metal hydride and the tetrahydro-
furan was evaporated in vacuo. The alkaline aqueous solution
was washed with ethyl acetate or diethyl ether (2 x 100 ml) and
acidified to pH 1 with 6 N hydrochloric acid. Dichloromethane

325
Synthesis of Lariat Ether Carboxylic Acids Based on Dibenzo-16-crown-5
Mar-Apr 2001
(30 ml) was added and the organic layer was separated, dried
over magnesium sulfate and evaporated in vacuo.
Compounds 16 and 20 were crystallized from ethanol.
Compounds 17, 19, 23, 26, 30-32, 34, 35, and 37 were
crystallized from ethyl acetate-hexanes. Compounds 24, 28 and
30 were crystallized from diethyl ether.
(40 ml) was added over a 10-minute period and the mixture was
stirred at room temperature for 2 hours. A solution of
bromoacetic acid (0.86 g. 6.22 mmoles) in 10 ml of tetrahydro-
furan was added over a 1-hour period and the mixture was stirred
at room temperature for 4 hours. The mixture was cooled to 0°
and ice-water (20 ml) was added dropwise to destroy the
unreacted potassium hydride. The tetrahydrofuran was
evaporated in vacuo and sufficient water was added to dissolve
the residue. The alkaline aqueous solution was washed with
diethyl ether (3 x 40 ml) and extracted with ethyl acetate (60 ml,
then 2 x 30 ml). (The 1-hexynyl product salt was extracted with
80-ml portions of ethyl acetate until no more product could be
extracted, as determined by tlc.) To the combined ethyl acetate
extracts, water (25 ml) was added and the mixture was acidified
to pH 1 with 1 N hydrochloric acid. The organic layer was
separated, washed with water (2 x 25 ml), dried over magnesium
sulfate and evaporated in vacuo. The crude product was dissolved
in a minimum amount of gently boiling ethyl acetate and hexanes
were added to the hot solution until a slight cloudiness persisted.
The mixture was heated again to obtain a solution that was
allowed to cool to room temperature. Additional hexanes were
added to give a total of about 60 ml. The mixture was allowed to
stand at room temperature overnight and then was filtered. If
further purification was needed, the product was recrystallized
from diethyl ether. The yields and physical, spectral and analysis
data for compounds 54-58 are given in Table 4.
The yields and physical, spectral and analysis data are given in
Table 2.
General Procedure for the Preparation of sym-(Aryl)- or
(Aralkyl)dibenzo-16-crown-5-oxyacetic Acids 38-50.
Tetrahydrofuran (30 ml) was added to 1.44 g (60 mmoles) of
dry sodium hydride or 2.46 g (60 mmoles) of potassium hydride
(which had been washed with pentane to remove the mineral oil)
under nitrogen and the metal hydride was suspended in tetra-
hydrofuran (20 ml). The lariat ether alcohol (6.0 mmoles) [27] in
tetrahydrofuran (50 ml) was added dropwise over a 1-hour
period. The mixture was stirred at room temperature for an
additional hour and a solution of bromoacetic acid (1.66 g,
12 mmoles) in tetrahydrofuran (25 ml) was added dropwise over
a 2-hour period. The mixture was stirred at room temperature for
12-24 hours. The excess of metal hydride was destroyed by
careful addition of water and the tetrahydrofuran was evaporated
in vacuo. The alkaline aqueous solution was extracted with
diethyl ether (2 x 100 ml) to remove the unreacted lariat ether
alcohol, acidified to pH 1 with 6 N hydrochloric acid and
extracted with dichloromethane (2 x 60 ml). The combined
organic layers were washed with water, dried over magnesium
sulfate and evaporated in vacuo to give a white to pale yellow
solid that was purified by recrystallization from ethyl acetate-
hexanes to give a white solid. The yields and physical, spectral
and analysis data are given in Table 3.
Preparation of Di(aminobenzo)-16-crown-5-oxyacetic Acid (61).
Di(nitrobenzo)-16-crown-5-oxyacetic acid (60) (10.0 g,
20.2 mmoles) [33] was mixed with 300 ml of ethanol and 2.4 g of
5% Pd/C and then 70 ml of 85% hydrazine hydrate were added.
The mixture was refluxed for 24 hours and filtered. The volume
of the filtrate was reduced in vacuo. After standing overnight, a
white solid was filtered and washed with ethanol. The filtrate was
reduced in volume and yielded additional product. The yield and
physical, spectral and analysis data for very hygroscopic 61 are
given in Table 5.
General Procedure for the Preparation of sym-(Alkenyl)dibenzo-
16-crown-5-oxyacetic Acids 51-53.
The protecting mineral oil from sodium hydride (1.26 g,
32 mmoles, 60% dispersion in mineral oil) was removed by
washing with pentane (2 x 20 ml) and tetrahydrofuran (25 ml)
was added. The lariat ether alcohol (5.24 mmoles) [27] in
tetrahydrofuran (20 ml) was added dropwise and the mixture was
stirred for 1 hour. After a solution of bromoacetic acid (1.46 g,
10.5 mmoles) in tetrahydrofuran (20 ml) was added dropwise, the
reaction mixture was stirred overnight at room temperature and
then refluxed for 6 hours. After cooling to room temperature,
water (40 ml) was added carefully to destroy the excess of
sodium hydride. The tetrahydrofuran was evaporated in vacuo
and the alkaline aqeuous mixture was acidified to pH 1 with 6 N
hydrochloric acid. The aqueous solution was extracted with
dichloromethane (2 x 60 ml). The combined dichloromethane
extracts were dried over magnesium sulfate and evaporated in
vacuo. Compounds 51 and 52 were recrystallized from ethanol
and diethyl ether, respectively. The yields and physical, spectral
and analysis data are given in Table 4.
Preparation of sym-(Methyl)di[4(5)-tert-butylbenzo]-16-crown-
5-oxyacetic Acid (63).
Under nitrogen, 1.00 g (21.3 mmoles) of sodium hydride (60%
dispersion in mineral oil) was washed three times with pentane to
remove the mineral oil and was suspended in tetrahydrofuran
(50 ml). To the stirred mixture, 5.3 mmoles of sym-(hydroxy)-
(methyl)dibenzo-16-crown-5 [27] in 50 ml of tetrahydrofuran
was added over a 15-minute period and the mixture was stirred
for 1 hour. A solution of 1.64 g (11.8 mmoles) of bromoacetic
acid in tetrahydrofuran (25 ml) was added dropwise followed by
stirring at room temperature for 48 hours and then refluxing for 1
hour. Water (50 ml) was added to the cooled reaction mixture fol-
lowed by addition of 6 N hydrochloric acid to pH 1 and stirring
for 2 hours. The tetrahydrofuran was evaporated in vacuo and the
resultant aqueous mixture was extracted with dichloromethane
(3 x 10 ml). The combined dichloromethane extracts were dried
over magnesium sulfate and evaporated in vacuo to give a crude
product that was chromatographed twice on silica gel with
dichloromethane-methanol (10:1) as eluent. Recrystallization
from ethyl acetate-petroleum ether (bp 30-60°) (1:10) gave a
white crystalline solid. The yield and physical, spectral and
analysis data for 63 are given in Table 5.
General Procedure for the Synthesis of sym-(1-Alkynyl)dibenzo-
16-crown-5-oxyacetic Acids 54-58.
Under nitrogen, potassium hydride (2.37 g, 35 wt. % disper-
sion in mineral oil, 21 mmoles) was washed with pentane to
remove the protecting mineral oil and tetrahydrofuran (40 ml)
was added. A solution of the sym-(1-alkynyl)(hydroxy)dibenzo-
16-crown-5 compound (4.14 mmoles) [27] in tetrahydrofuran

326
Vol. 38
R. A. Bartsch, C. L. Cowey, S. Elshani, M.-J. Goo, V. J. Huber, S. N. Ivy,
R. J. Johnson, J. S. Kim, E. Luboch, J. A. McDonough, M. J. Pugia, B. Son and Q. Zhao
Preparation of sym-(Propyl)di(nitrobenzo)-16-crown-5-oxyacetic
Acid (64).
reaction solution for 72 hours for 84 and 12 hours for 85. At
room temperature, water (50 ml) was added. After stirring for
5 minutes, the reaction solution was extracted with
dichloromethane (3 x 50 ml). The combined dichloromethane
extracts were washed with water (50 ml), dried over magnesium
sulfate and evaporated in vacuo.
To a stirred suspension of 8.89 g (19.9 mmoles) of sym-
(propyl)dibenzo-16-crown-5-oxyacetic acid (15) [14] in 80 ml of
glacial acetic acid-chloroform (1:1), a solution of 13.5 ml of
concentrated nitric acid and 4.5 ml of water was added dropwise
at room temperature. The reaction mixture was stirred at room
temperature for 2 hours, poured into water (300 ml) and extracted
with dichloromethane (2 x 150 ml). The combined
dichloromethane extracts were washed with water (6 x 100 ml),
dried over magnesium sulfate and evaporated to afford a yellow
solid. The yield and physical, spectral and analysis data for 64 are
given in Table 5.
Methyl 3-(sym-dibenzo-16-crown-5-oxy)propanoate (86).
Compound 86 was obtained in 94% yield as an orange oil after
chromatography on silica gel with dichloromethane–diethyl ether
-1 1
(1:1) as eluent; ir (neat): ν 1739 (C=O), 1130 (C-O) cm ; H nmr
(deuteriochloroform): δ 2.69-2.75 (t, 2H, J=6Hz), 3.65-4.41
(m, 18H), 6.75-7.10 (m, 8H). Combustion analyses for lariat
ether ester 86 was not performed, but satisfactory combustion
analysis results were obtained for lariat carboxylic acid 68.
Preparation of 1-Cyano-2-(sym-dibenzo-16-crown-5-oxy)-
ethane (84).
Methyl 3-(sym-di[4(5)-tert-butylbenzo]-16-crown-5-oxy)-
propanoate (87.
Under nitrogen at room temperature with the exclusion of
light, sym-(hydroxy)dibenzo-16-crown-5 (82) (3.00 g,
8.57 mmoles) [35] was dissolved in 30 ml of acrylonitrile.
Potassium tert-butoxide (0.26 g, 2.34 mmoles) was added and
the reaction solution was stirred for 4 hours. Hydrochloric
acid (3 N, 60 ml) was added. The mixture was filtered and the
filtrate was extracted with dichloromethane (3 x 30 ml). The
combined dichloromethane extracts were dried over
magnesium sulfate and evaporated in vacuo. The residue was
chromatographed on silica gel with diethyl ether as eluent.
The resultant clear oil was triturated with 2 drops of methanol
to give 2.15 g (63%) of white solid with mp 116-117°: ir
(deposit from dichloromethane on a sodium chloride plate):
Compound 87 was isolated in 74% yield as a brown oil after
chromatography on alumina with diethyl ether as eluent; ir
-1
1
(neat): ν 1739 (C=O) cm ; H nmr (deuteriochloroform): δ 1.28
(s, 18H), 2.70-2.79 (m, 2H), 3.69 (s, 3H), 3.80-4.48 (m, 15H),
6.78-7.18 (m, 6H).
Anal. Calcd. for C
H O : C, 68.37; H, 8.14. Found: C,
31 44 8
68.57; H, 8.18.
General Procedure for the Preparation of Lariat Ether Carboxylic
Acids 68 and 69.
The lariat ether ester 86 or 87 (1.37 mmoles) was dissolved in
70 ml of 95% ethanol at room temperature and a solution of
potassium hydroxide (0.15 g, 2.74 mmoles) dissolved in 5 ml of
water was added. The reaction solution was stirred for 15 minutes
and concentrated hydrochloric acid was added to pH 6. The
solution was evaporated in vacuo and the residue was dissolved
in dichloromethane (30 ml). The dichloromethane solution was
dried over magnesium sulfate and evaporated in vacuo. The
residue was recrystallized from benzene to give 68 as a white
solid. Compound 69 was obtained as an oil which solidified on
standing. The yields and physical, spectral and analysis data for
68 and 69 are given in Table 6.
-1
1
ν 2251 (C≡N), 1132 (C-O) cm
;
H nmr (deuterio-
chloroform): δ 2.71-2.74 (t, 2H, J = 6Hz), 3.71-4.45 (m, 15H),
6.84-7.26 (m, 8H).
Anal. Calcd. for C
H NO : C, 66.14; H, 6.31. Found: C,
22 25 6
65.90; H, 6.41.
Preparation of 1-Cyano-2-(sym-di[4(5)-tert-butylbenzo]-16-
crown-5-oxy)ethane (85).
Under nitrogen at room temperature, sym-(hydroxy)di[4(5)-
tert-butylbenzo]-16-crown-5 (83) (0.49 g, 1.09 mmoles) [32] and
potassium tert-butoxide (0.01 g, 0.09 mmoles) were dissolved in
tetrahydrofuran (49 ml). A solution of acrylonitrile (0.29 g,
5.44 mmoles) in tetrahydrofuran (20 ml) was added over a
20-minute period. The reaction mixture was stirred for 12 hours
at room temperature and the solvent was removed in vacuo. The
brown residue was dissolved in dichloromethane (30 ml), washed
with 6 N hydrochloric acid (20 ml), dried over magnesium sulfate
and chromatographed on alumina with diethyl ether-ethyl acetate
(5:1) as eluent to give 0.27 g (48%) of a clear oil; ir (neat): ν 2251
General Procedure for the Preparation of Lariat Ether Mesylates
91-93.
To a solution of 2.90 mmoles of the appropriate lariat ether
alcohol [27] and 0.45 g (4.40 moles) of triethylamine in 100 ml of
dichloromethane at 0° under nitrogen was added dropwise
methanesulfonyl chloride (0.51 g, 4.40 mmoles) during a
30-minute period. After stirring for an additional 2 hours, water
(100 ml) was added. The dichloromethane layer was separated,
washed with 5% hydrochloric acid (30 ml), 5% aqueous sodium
bicarbonate (30 ml), and brine (50 ml), dried over magnesium
sulfate and evaporated in vacuo to give the lariat ether mesylate
as a colorless oil.
-1
1
(C≡N) cm ; H nmr (deuteriochloroform): δ 1.14 (s, 18H),
2.51-2.69 (m, 2H), 3.54-4.45 (m, 15H), 6.51-7.02 (m, 6H).
Anal. Calcd. for C
H NO : C, 70.42; H, 8.08. Found: C,
30 41 6
70.58; H, 8.28.
General Procedure for the Preparation of Lariat Ether Esters 86
and 87.
2-[sym-(Methyl)dibenzo-16-crown-5-oxy]ethyl mesylate (91).
Compound 91 was obtained in 90% yield; ir (neat): ν 1350
Under nitrogen in a flask equipped with a fritted glass bubbler
and an adapter that passed the condensate through a thimble
filled with anhydrous sodium sulfate, a solution of lariat ether
nitrile 84 or 85 (1.00 mmole) in methanol (100 ml) was brought
to reflux. Hydrogen chloride gas was bubbled through the
-1
1
(S=O), 1123 (C-O) cm ; H nmr (deuteriochloroform): δ 1.50
(s, 3H), 3.03 (s, 3H), 3.38-4.43 (m, 16H), 6.82-6.99 (m, 8H).
Anal. Calcd. for C
H SO : C, 57.26; H, 6.27. Found: C,
23 30 9
56.87; H, 6.09.

327
Synthesis of Lariat Ether Carboxylic Acids Based on Dibenzo-16-crown-5
Mar-Apr 2001
3-(sym-Dibenzo-16-crown-5-oxy)propyl mesylate (92).
thimble containing anhydrous sodium sulfate, hydrogen chloride
gas was bubbled for 24 hours. After the methanol was evaporated
in vacuo, water (20 ml) and ethyl acetate (30 ml) were added to
the residue and the mixture was shaken. The organic layer was
separated, washed with 5% aqueous sodium bicarbonate
(3 x 30 ml), dried over magnesium sulfate and evaporated in
vacuo to give a colorless oil.
Compound 92 was isolated in 95% yield; ir (neat): ν 1361,
-1
1
1176 (SO ), 1251, 1140 (C-O) cm
; H nmr (deuterio-
2
chloroform): δ 1.85-2.15 (m, 2H), 2.95 (s, 3H), 3.81-4.52
(m, 17H), 6.81-6.98 (m, 8H).
Anal. Calcd. for C
H O S: C, 57.25; H, 6.27. Found: C,
23 30 9
57.04; H, 6.10.
Methyl 3-[sym-(methyl)dibenzo-16-crown-5-oxy]propionate (97).
3-[sym-(Methyl)dibenzo-16-crown-5-oxy]propyl mesylate (93).
Compound 93 was obtained in 94% yield; ir (neat): ν 1353,
1174 (S=O), 1123 (C-O) cm ; H nmr (deuteriochloroform): δ
1.49 (s, 3H), 1.93-2.06 (m, 2H), 2.90 (s, 3H), 3.88-4.40 (m, 16H),
6.80-6.96 (m, 8H),
Compound 97 was obtained in 65% yield as a colorless oil
after chromatography on silica gel with ethyl acetate-hexanes
-1
1
-1 1
(1:4) as eluent; ir (neat): ν 1737 (C=O), 1122 (C-O) cm ; H nmr
(deuteriochloroform): δ 1.52 (s, 3H), 2.62-2.65 (t, 2H, J = 6Hz),
3.67 (s, 3H), 3.70-4.24 (m, 14H), 6.81-6.99 (m, 8H).
Anal. Calcd. for C
H O S: C, 58.06; H, 6.49. Found: C,
24 32 9
Anal. Calcd. for C
H 0 : C, 64.57; H, 6.77. Found: C, 64.70;
23 30 8
58.28; H, 6.25.
H, 6.64.
General Procedure for the Preparation of Lariat Ether Nitriles 94-96.
Methyl 4-(sym-dibenzo-16-crown-5-oxy)butanoate (98).
To a solution of 4.10 mmoles of lariat ether mesylate 91, 92
or 93 in dimethyl sulfoxide (30 ml) was added 0.61 g
(12.4 mmoles) of sodium cyanide and the reaction mixture was
stirred for 2 days at 45° for 91 and 92 and at 90° for 93. At
room temperature, diethyl ether (20 ml) and water (30 ml) were
added and the mixture was shaken. The organic layer was
separated, washed with water (6 x 30 ml) and brine (3 x 30 ml),
dried over magnesium sulfate and evaporated in vacuo to give
a colorless oil.
Compound 98 was isolated as a tan oil in 79% yield after
chromatography on silica gel with dichloromethane then
diethyl ether as eluents; ir (neat): ν 1734 (C=O), 1123 (C-O)
cm ; H nmr deuteriochloroform: δ 1.98 (p, 2H), 2.51-2.54
(t, 2H, J = 6Hz), 3.65 (s, 3H) 3.71-4.31 (m, 15H), 6.80-7.00
(m, 8H).
-1
1
Anal. Calcd. for C
H 0 : C, 64.56; H, 6.77. Found: C, 64.72;
24 30 8
H, 6.61.
Methyl 4-[sym-(methyl)dibenzo-16-crown-5-oxy]butanoate (99).
3-[sym-(Methyl)dibenzo-16-crown-5-oxy]propanonitrile (94).
Compound 99 was obtained in 94% yield as a colorless oil
Compound 94 was obtained in 60% yield as a colorless oil
after chromatography on silica gel with ethyl acetate-hexanes
after chromatography on silica gel with ethyl acetate-hexanes
-1 1
(1:4) as eluent; ir (neat): ν 1733 (C=O), 1124 (C-O) cm ; H nmr
-1 1
(1:5) as eluent; ir (neat): ν 2248 (C≡N), 1123 (C-O) cm ; H nmr
(deuteriochloroform): δ 1.49 (s, 3H), 1.95 (m, 2H), 2.47-2.50
(t, 2H, J = 6Hz), 3.62 (s, 3H), 3.79-3.82 (t, 2H, J = 6Hz),
3.91-3.95 (m, 4H), 4.10-4.23 (m, 8H), 6.81-6.96 (m, 8H).
(deuteriochloroform): δ 1.51 (s, 3H), 2.62-2.65 (t, 2H, J = 6Hz),
3.98-4.43 (m, 14H), 6.82-6.99 (m, 8H).
Anal. Calcd. for C
H NO : C, 66.81; H, 6.58. Found: C,
23 27 6
Anal. Calcd. for C
H 0 : C, 65.20; H, 7.00. Found: C, 65.21;
24 32 8
66.88; H, 6.77.
H, 6.99.
4-(sym-Dibenzo-16-crown-5-oxy)butanonitrile (95).
General Procedure for the Preparation of Lariat Ether Carboxylic
Compound 95 was isolated in 74% yield as a colorless oil after
chromatography on alumina with diethyl ether then diethyl ether-
ethyl acetate (5:1) as eluents; ir (neat): ν 2247 (C≡N), 1124 (C-O)
Acids 70-72.
A solution of the lariat ether ester 97, 98 or 99 (102 mmoles),
0.01 g (0.25 mmoles) of potassium hydroxide and 10 ml of 95%
ethanol was stirred for 1 hour at room temperature. After
evaporation in vacuo, ethyl acetate (10 ml) and water (10 ml)
were added to the residue. The aqueous layer was separated,
washed with ethyl acetate (3 x 10 ml) and acidified to pH 1 with
6 N hydrochloric acid followed by addition of dichloromethane
(10 ml). The organic layer was dried over magnesium sulfate and
evaporated in vacuo to give a colorless oil. Compounds 70 and 72
were crystallized from benzene, while compound 71 solidified on
standing. The yields and physical, spectral and analysis data for
70-72 are given in Table 6.
-1
1
cm ; H nmr (deuteriochloroform): δ 1.99 (p, 2H), 2.55-2.58
(t, 2H, J = 6Hz), 3.70-4.45 (m, 15H), 6.72-7.05 (m, 8H).
Anal. Calcd. for C
H NO : C, 66.81; H, 6.58. Found: C,
23 27 6
66.84; H, 6.68.
4-[sym-(Methyl)dibenzo-16-crown-5-oxy]butanonitrile (96).
Compound 96 was obtained in 84% yield as a white solid with
mp 109-110° after chromatography on silica gel with ethyl
acetate-hexanes (1:5) as eluent; ir (deposit from dichloromethane
solution on a sodium chloride plate): ν 2246 (C≡N), 1123 (C-O)
-1
1
cm ; H nmr (deuteriochloroform): δ 1.49 (s, 3H), 1.86-1.97
(m, 2H), 2.50-2.53 (t, 2H, J = 6Hz), 3.85-4.31 (m, 14H),
6.82-6.99 (m, 8H).
General Procedure for the Preparation of Vinylidene Dibenzo
Crown Ethers 102 and 103.
Anal. Calcd. for C
67.51; H, 6.64.
H NO : C, 67.43; H, 6.84. Found: C,
24 29 6
Procedure A (regular addition).
Under nitrogen, bisphenol 100 [41] or 101 [32] (2.48 mmoles)
was dissolved in acetonitrile (11 ml) and cesium carbonate (1.78 g,
5.48 mmoles) was added. The mixture was heated to 80° and a
solution of methallyl dichloride (0.47 g, 3.76 mmoles) dissolved in
acetonitrile (5.4 ml) was added during a 30-hour period with a
General Procedure for the Preparation of Lariat Ether Esters 97-99.
Into a refluxing solution of the lariat ether nitrile 94, 95 or 96
(1.69 mmole) in methanol (50 ml) in a flask fitted with a fritted
glass bubbler and an adapter to pass the condensate through a

328
Vol. 38
R. A. Bartsch, C. L. Cowey, S. Elshani, M.-J. Goo, V. J. Huber, S. N. Ivy,
R. J. Johnson, J. S. Kim, E. Luboch, J. A. McDonough, M. J. Pugia, B. Son and Q. Zhao
syringe pump. The reaction mixture was stirred for a total of 3 days
and then cooled to room temperature. A solution of 3 N potassium
hydroxide (30 ml) was added and the mixture was extracted with
dichloromethane (3 x 30 ml). The combined dichloromethane
extracts were dried over magnesium sulfate and evaporated in vacuo.
The residue was chromatographed on alumina with
dichloromethane-diethyl ether (varying ratios) as eluent.
-1 1
sodium chloride plate): ν 3600-3200 (OH), 1123 (C-O) cm ; H
nmr (deuteriochloroform): δ 2.48 (m, 1H), 2.77 (br s, OH, 1H),
3.71-4.45 (m, 14H), 6.65-6.95 (m, 8H).
sym-(Hydroxymethyl)di[4(5)-tert-butylbenzo]-16-crown-5 (105).
Under nitrogen at 0°, to a solution of vinylidene crown ether
103 (0.83 g, 1.82 mmoles) in tetrahydrofuran (15 ml) and sodium
borohydride (0.07 g, 1.85 mmoles) was added. Then boron
trifluoride-diethyl etherate (0.26 g, 18.21 mmoles) was added
with a syringe and the reaction mixture was stirred for 2 hours.
The mixture was allowed to warm to room temperature and was
stirred for 14 hours. The mixture was cooled to 0° and ice was
added until hydrogen evolution ceased. A 2 N sodium hydroxide
solution (0.91 ml) and then 30% hydrogen peroxide (3.59 ml)
were added and the mixture was warmed to room temperature.
The reaction mixture was stirred for 2 days and the tetrahydro-
furan was evaporated in vacuo. The resultant aqueous residue
was extracted with dichloromethane (3 x 30 ml). The combined
dichloromethane extracts were washed with 5% hydrochloric
acid (20 ml), dried over magnesium sulfate and evaporated in
vacuo. The residue was chromatographed on alumina with
diethyl ether then ethyl acetate as eluents to give 0.40 g (45%) of
a low-melting, colorless solidified oil (attempted recrystallization
from methanol was unsuccessful); ir (deposit from
dichloromethane solution on a sodium chloride plate): ν 3518
Procedure B (simultaneous addition).
The bisphenol (13.92 mmoles) was diluted to 30 ml with
acetonitrile and taken up in a syringe. Methallyl dichloride (2.61
g, 20.88 mmoles) was diluted to 30 ml with acetonitrile and taken
up in another syringe. The two solutions were simultaneously
added with two syringe pumps during a 20-hour period to a
stirred suspension of cesium carbonate (9.98 g, 30.71 mmoles) in
acetonitrile (40 ml) at 80°. The reaction mixture was stirred for a
total of 3 days and cooled to room temperature. A 3 N solution of
potassium hydroxide (30 ml) was added and the mixture was
extracted with dichloromethane (3 x 30 ml). The combined
dichloromethane extracts were dried over magnesium sulfate and
evaporated in vacuo. The residue was chromatographed on
alumina with dichloromethane-diethyl ether (varying ratios) as
eluent.
sym-(Vinylidene)dibenzo-16-crown-5 (102).
-1
1
(OH), 1146 (C-O) cm ; H nmr (deuteriochloroform): δ 1.27
(s, 18H), 2.41-2.69 (m, 1H), 2.70-2.90 (br s, 1H, OH), 3.62-4.44
(m, 14H), 6.68-7.08 (m, 6H).
Compound 102 was obtained as a white solid with mp 94-95°
(lit mp [42] 94-95°) in 60% yield by Procedure A and 72% yield
by Procedure B; ir (deposit from dichloromethane solution on a
-1
1
Anal. Calcd. for C
H O •CH OH: C, 69.02; H, 8.79. Found:
sodium chloride plate): ν 1661, 1120 (C-O) cm ; H nmr
(deuteriochloroform): δ 3.83-4.04 (m, 4H), 4.11-4.31 (m, 4H),
4.77-4.80 (d, 4H,J = 8Hz), 5.44 (s, 2H), 6.75-7.10 (m, 8H).
28 40 6 3
C, 69.06; H, 8.77.
sym-(Mesyloxymethyl)dibenzo-16-crown-5 (106).
sym-(Vinylidene)di[4(5)-tert-butylbenzo]-16-crown-5 (103).
To a solution of lariat ether alcohol 104 (0.89 g, 2.47 mmoles)
and triethylamine (0.50 g, 4.94 mmoles) in dichloromethane
(22 ml) under nitrogen at -10°, a solution of mesyl chloride
(0.57 g, 4.94 mmoles) in dichloromethane (22 ml) was added
dropwise during a 30-minute period. The reaction mixture was
stirred for 1 hour at 0° and for 15 hours at room temperature and
then 5% hydrochloric acid (60 ml) was added. The mixture was
extracted with dichloromethane (2 x 20 ml) and the combined
dichloromethane extracts were washed with 5% sodium
bicarbonate (3 x 40 ml), dried over magnesium sulfate and
evaporated in vacuo to give 1.06 g (98%) of a cloudy, low
Compound 103 was obtained as translucent colorless oil in
74% yield by Procedure A and in 55% yield by Procedure B; ir
-1
1
(neat): ν 1654, 1120 (R C=CH ), 1146 (C-O) cm ; H nmr
2
2
(deuteriochloroform): δ 1.27 (s, 18H), 3.73-3.92 (m, 4H),
3.97-4.33 (m, 4H), 4.75-4.79 (d, 4H, J = 8Hz), 5.42-5.45 (m, 2H),
6.68-7.12 (m, 6H).
Anal. Calcd. for C
H O : C, 73.98; H, 8.42. Found: C,
28 38 5
74.23; H, 8.31.
sym-(Hydroxymethyl)dibenzo-16-crown-5 (104).
melting, solidified oil; ir (neat): ν 1359, 1175 (SO ), 1124 (C-O)
2
Under nitrogen at 0°, to a solution of vinylidene crown ether
102 (1.55 g, 4.54 mmoles) in tetrahydrofuran (45 ml), a 1.0 M
solution of borane-tetrahydrofuran (11.07 ml) was added
dropwise over a 10-minute period. The solution was warmed to
room temperature and the solution was stirred for 48 hours. After
cooling to 0°, 30% hydrogen peroxide (8 ml) and then a 2 N
sodium hydroxide solution (3 ml) were added. The solution was
stirred for 24 hours at room temperature. After adding 2 N
sodium hydroxide (51 ml), the reaction mixture was refluxed for
48 hours, cooled to room temperature and extracted with
dichloromethane (3 x 30 ml). The combined dichloromethane
extracts were dried over magnesium sulfate and evaporated in
vacuo. The residue was chromatographed on alumina with ethyl
acetate then ethyl acetate-methanol (15:1) as eluents. The
colorless residue was recrystallized from heptane-benzene to
give 0.99 g (60%) of a white solid with mp 110° (lit mp
[42] 110-111°); ir (deposit from a dichloromethane solution on a
-1
1
cm ; H nmr (deuteriochloroform): δ 2.65-2.86 (m, 1H), 3.01
(s, 3H), 3.75-4.00 (m, 4H), 4.00-4.35 (m, 8H), 4.73-4.78 (d, 2H,
J = 10Hz), 6.75-7.03 (m, 8H).
Anal. Calcd. for C
Found: C, 53.50; H, 5.47.
H O S•0.35 CDCl : C, 53.39; H, 5.53.
21 26 8 3
(sym-Dibenzo-16-crown-5)ethanonitrile (107).
Under nitrogen at room temperature, to a solution of lariat ether
mesylate 106 (0.68 g, 1.55 mmoles) in dimethyl sulfoxide (11 ml),
sodium cyanide (0.23 g, 4.67 mmoles) was added. The mixture was
heated to 60°, stirred for 36 hours and cooled to room temperature.
Water (20 ml) was added and the solution was extracted with
dichloromethane (4 x 20 ml). The dichloromethane extracts were
combined, washed with 3 N hydrochloric acid (20 ml), dried over
magnesium sulfate and evaporated in vacuo. The residue was
chromatographed on alumina with dichloromethane-diethyl ether
(1:1) as eluent to give 0.56 g (98%) of a white solid with mp

329
Synthesis of Lariat Ether Carboxylic Acids Based on Dibenzo-16-crown-5
Mar-Apr 2001
108-109°; ir (deposit from a dichloromethane solution on a sodium
Preparation of sym-(Bromo)dibenzo-16-crown-5 (110).
-1 1
chloride plate): ν 2246 (C≡N), 1123 (C-O) cm ; H nmr (deuterio-
Under nitrogen, lariat ether tosylate 109 (2.83 g, 5.65 mmoles),
lithium bromide (4.91 g, 56.5 moles) and water (3.5 ml) were
dissolved in hexamethylphosphoramide (80 ml). The solution
was stirred at 100° for 16 hours and then cooled to room
temperature. After addition of 6 N hydrochloric acid (100 ml),
the mixture was extracted with dichloromethane (2 x 40 ml). The
combined dichloromethane extracts were washed with 6 N
hydrochloric acid (2 x 100 ml), dried over magnesium sulfate and
evaporated in vacuo. The residue was chromatographed on
alumina with dichloromethane as eluent to give 1.91 g (83%) of
white solid with mp 83-84°; ir (deposit from a dichloromethane
solution on a sodium chloride plate): ν 1126 (C-O), 748 (C-Br)
chloroform): δ 2.55-2.78 (m, 1H), 2.94-2.99 (d, 2H, J = 6Hz),
3.75-4.05 (m, 4H), 4.05-4.37 (m, 8H), 6.69-7.09 (m, 8H).
Anal. Calcd. for C
H NO : C, 68.28; H, 6.28. Found: C,
21 23 5
68.19; H, 6.26.
Methyl (sym-Dibenzo-16-crown-5)acetate (108).
Under nitrogen in a flask equipped with a fritted glass bubbler
and an adapter that passed the condensate through a thimble
filled with anhydrous sodium sulfate, lariat ether nitrile 107
(0.20 g, 0.73 mmoles) was dissolved in methanol (80 ml). At
reflux, hydrogen chloride gas was bubbled through the solution
for 16 hours. The solution was cooled to room temperature and
water (10 ml) was added. The mixture was stirred for 1 hour and
extracted with dichloromethane (3 x 20 ml). The combined
dichloromethane extracts were washed with water (10 ml), dried
over magnesium sulfate and evaporated in vacuo. The residue
was chromatographed on silica gel with dichloromethane-diethyl
ether (2:1) as eluent to give 0.29 g (98%) of a cream-colored
solid with mp 87-88°; ir (deposit from dichloromethane solution
-1
1
cm , H nmr (deuteriochloroform): δ 3.84-3.87 (t, 4H, J = 6Hz),
4.09-4.12 (t, 4H, J = 6Hz), 4.21-4.55 (m, 2H), 4.55-4.68 (m, 3H),
6.79-7.05 (m, 8H).
Anal. Calcd. for C
Found: C, 46.84; H, 4.52.
H O Br•1.3CH Cl : C, 46.91; H, 4.58.
19 21 5 2 2
Preparation of 3-(sym-Dibenzo-16-crown-5)propanoic Acid (75).
Under deoxygenated nitrogen in a 10-ml pyrex flask, lariat
ether bromide 110 (0.18 g, 0.43 mmoles) was dissolved in 2 ml of
deoxygenated tetrahydrofuran and freshly distilled acrylic acid
(0.030 g, 0.43 mmoles) was added. The reaction mixture was
irradiated with a 500-watt sun lamp placed 20 cm from the
reaction vessel and tributyltin hydride (0.13 g, 0.43 mmoles) was
added during a 5-hour period with a syringe pump. The reaction
solution was stirred overnight at room temperature in the dark. A
solution of acrylic acid (0.030 g, 0.43 mmoles) in tetrahydrofuran
(2 ml) was added. The reaction solution was irradiated again and
tributyltin hydride (0.13 g, 0.43 mmoles) was added during a
6-hour period with a syringe pump. Dichloromethane (30 ml)
was added and the mixture was washed with 5% sodium bicar-
bonate (25 ml) and 3 N hydrochloric acid (25 ml). The solvent
was evaporated in vacuo and the brown residue was subjected to
-1
1
on a sodium chloride plate): ν 1732 (C=O), 1122 (C-O) cm ; H
nmr (deuteriochloroform): δ 2.70-3.02 (m, 3H), 3.69 (s, 3H),
3.70-4.05 (m, 4H), 4.05-4.35 (m, 8H), 6.69-7.09 (m, 8H).
Anal. Calcd. for C
H O : C, 65.66; H, 6.47. Found: C,
22 26 7
65.40; H, 6.52.
(sym-Dibenzo-16-crown-5)acetic Acid (74).
Under nitrogen at room temperature, lariat ether ester 108
(0.25 g, 0.62 mmoles) was dissolved in 30 ml of 95% ethanol
and 3 N potassium hydroxide (4.14 ml) was added. The solution
was stirred for 1 hour at room temperature and evaporated in
vacuo. The residue was dissolved in dichloromethane (30 ml)
and washed with 6 N hydrochloric acid (30 ml). The
dichloromethane solution was dried over magnesium sulfate
and the solvent was removed in vacuo to give 0.24 g (99%) of a
low-melting, white, solidified oil. Spectral and analysis data for
74 are given in Table 7.
radial chromatography on
a silica gel plate using
dichloromethane, diethyl ether-dichloromethane (1:1), diethyl
ether, then diethyl ether-methanol (1:1) as eluents to give a white
solid. The solid was dissolved in dichloromethane (50 ml) and
extracted with 10% sodium hydroxide (5 x 20 ml). The combined
sodium hydroxide extracts were acidified with concentrated
hydrochloric acid to pH 1 and extracted with dichloromethane
(3 x 30 ml). The combined dichloromethane extracts were dried
over magnesium sulfate and evaporated in vacuo to give a white
solid. Spectral and analysis data for 75 are given in Table 7.
Preparation of sym-(Tosyloxy)dibenzo-16-crown-5 (109).
Under nitrogen at room temperature, sym-hydroxydibenzo-
16-crown-5 (82) (5.00 g, 14.4 mmoles) [35] and pyridine
(2.96 g, 37.4 mmoles) were dissolved in 15 ml of
dichloromethane. A solution of tosyl chloride (7.14 g,
37.4 moles) in dichloromethane (7.5 ml) was added over a
30-minute period. The mixture was stirred for 24 hours at
room temperature and 6 N hydrochloric acid (50 ml) was
added. The mixture was extracted with dichloromethane
(2 x 30 ml). The combined dichloromethane extracts were
washed with water (20 ml), dried over magnesium sulfate and
evaporated in vacuo. The residue was chromatographed on
alumina with diethyl ether as eluent to give 7.56 g (97%) of
white solid with mp 129-130°; ir (deposit): ν 1415, 1363
General Procedure for the Preparation of Lariat Ether Esters 111
and 112.
To a solution of lariat ether alcohol 104 or 105 (2.61 mmoles)
dissolved in tetrahydrofuran (24 ml) under nitrogen at room
temperature was added sodium hydride (0.063 g, 2.61 mmoles,
60% dispersion in mineral oil) suspended in tetrahydrofuran
(1 ml). After hydrogen evolution ceased, a solution of ethyl
bromoacetate (0.44 g, 2.61 mmoles) in tetrahydrofuran (3 ml)
was added dropwise over a 10-minute period. The reaction
mixture was stirred for 3 hours, refluxed for 5 minutes and
cooled to room temperature. Sodium hydride (0.63 g,
2.61 mmoles, 60% dispersion in mineral oil) and a solution of
ethyl bromoacetate (0.44 g, 2.61 mmoles) tetrahydrofuran (3 ml)
were added. The reaction mixture was refluxed for 2.5 hours and
-1
1
(SO ), 1147 (C-O) cm ; H nmr (deuteriochloroform): δ 2.26
2
(s, 3H), 3.86-3.91 (d, 4H, J = 10Hz), 4.08-4.13 (d, 4H, J =
10Hz), 4.28-4.33 (dd, 2H, J = 3, 10Hz), 4.42-4.47 (dd, 2H, J =
3, 10 Hz), 5.09 (p, 1H), 6.59-7.05 (m, 8H), 7.31-7.35 (d, 2H,
J = 8Hz), 7.90-7.94 (d, 2H, J = 8Hz).
Anal. Calcd. For C
Found: C, 61.61; H, 5.75.
H O S•0.5H O: C, 61.29; H, 5.74.
26 28 8 2

330
Vol. 38
R. A. Bartsch, C. L. Cowey, S. Elshani, M.-J. Goo, V. J. Huber, S. N. Ivy,
R. J. Johnson, J. S. Kim, E. Luboch, J. A. McDonough, M. J. Pugia, B. Son and Q. Zhao
then stirred for 15 hours at room temperature. Water (10 ml) was
added and the solution was extracted with dichloromethane
(3 x 30 ml). The combined dichloromethane extracts were dried
over magnesium sulfate and evaporated in vacuo. The residue
was chromatographed on alumina with carbon tetrachloride then
diethyl ether-ethyl acetate (20:1) as eluents to give the desired
product.
1-Amino-3-(sym-dibenzo-16-crown-5-oxy)propane (113).
Compound 113 was obtained in 54% yield as a waxy white
-1
1
solid; ir (neat): ν 3445, 3194, 1595 (NH), 1134 (C-O) cm ; H
nmr (deuteriochloroform): δ 1.87-2.04 (m, 2H), 3.01-3.20
(m, 2H), 3.75-4.35 (m, 15H), 6.51-7.05 (m, 10H).
1-Amino-3-(sym-di[4(5)-tert-butylbenzo]-16-crown-5-
oxy)propane (114).
Ethyl α-[sym-dibenzo-16-crown-5-methoxy]acetate (111).
Compound 114 was isolated in 40% yield as a pale green wax;
Compound 111 was obtained in 66% yield as a white solid
-1
1
ir (neat) ν 3389, 1600, 805 (NH), 1147 (C-O) cm ; H nmr
(deuteriochloroform): δ 1.27 (s, 18H), 2.01-2.04 (t, 2H, J = 6Hz),
3.15-3.18 (t, 2H, J = 6Hz), 3.71-4.45 (m, 15H), 6.69-7.02
(m, 6H), 7.58 (m, 2H).
with mp 96-97°; ir (deposit from dichloromethane solution on a
-1
sodium chloride plate): ν 1750 (C=O), 1122, 1139 (C-O) cm ;
1
H nmr (deuteriochloroform): δ 1.29-1.32 (t, 3H, J = 6Hz),
2.61-2.83 (m, 1H), 3.82-4.43 (m, 18H), 6.81-7.03 (m, 8H).
Although combustion analyses were not obtained for lariat
ether amines 113 and 114, satisfactory combustion analysis
results were obtained for lariat ether diesters 115 and 116,
respectively, which were prepared from these precursors.
Anal. Calcd. for C
H O : C, 64.56; H, 6.77. Found: C,
24 30 8
64.80; H, 6.64.
Ethyl α-[sym-di[4(5)-tert-butylbenzo]-16-crown-5-methoxy]-
acetate (112).
General Procedure for the Preparation of Lariat Ether Diesters
115 and 116.
Compound 112 was isolated in 40% yield as a colorless oil
which solidified on standing; ir (neat): ν 1752, 1734 (C=O),
1145 (C-O) cm ; H nmr (deuteriochloroform): δ 1.08-1.51
(m, 21H), 2.54-2.89 (m, 1H), 3.67-4.57 (m, 18H), 6.77-7.08
(m, 6H).
Under nitrogen, to a solution of lariat ether amine 113 or 114
(2.00 mmoles) and potassium carbonate (1.37 g, 9.94 mmoles) in
acetonitrile (83 ml), a solution of ethyl bromoacetate (0.99 g,
5.96 mmoles) in acetonitrile (2 ml) was added during a 10-minute
period. The reaction mixture was stirred for 48 hours at room
temperature and the solvent was removed in vacuo. The residue
was dissolved in dichloromethane (30 ml), washed with water
(2 x 50 ml), dried over sodium sulfate and evaporated in vacuo.
The residue was chromatographed on alumina with diethyl ether-
ethyl acetate (1:1) as eluent to give a clear oil.
-1
1
Anal. Calcd. for C
Found: C, 66.85; H, 8.17.
H O •0.25 CH Cl : C, 66.79; H, 8.08.
31 46 8 2 2
General Procedure for the Preparation of Lariat Ether Carboxylic
Acids 76 and 77.
To a solution of lariat ether ester 111 or 112 (1.70 mmoles) in
95% ethanol (125 ml) under nitrogen at room temperature, a
solution of potassium hydroxide (1.38 g, 24.6 mmoles) in water
(10 ml) was added. The solution was stirred for 9 hours at room
temperature and then acidified to pH 2 with concentrated
hydrochloric acid. The ethanol was evaporated in vacuo and
dichloromethane (30 ml) was added. The dichloromethane layer
was washed with water (20 ml), dried over magnesium sulfate
and evaporated in vacuo to give the desired product. Yields and
physical, spectral and analysis data for 76 and 77 are given in
Table 7.
1-[N,N-Di(ethylaceto)amino-3-(sym-dibenzo-16-crown-5-
oxy)]propane (115).
Compound 115 was obtained in 98% yield; ir (neat): ν 1747
-1
1
(C=O), 1147 (C-O) cm ; H nmr (deuteriochloroform): δ
1.25-1.28 (t, 6H, J = 6Hz), 1.84 (p, 2H), 2.91-2.94 (t, 2H, J =
6Hz), 3.58 (s, 4H), 3.79-4.45 (m, 19H), 6.81-7.01 (m, 8H).
Anal. Calcd. for C
H NO : C, 62.59; H, 7.18. Found: C,
30 41 10
62.50; H, 7.16.
1-[N,N-Di(ethylaceto)amino-3-(sym-di[4(5)-tert-butylbenzo]-
16-crown-5-oxy)]propane (116).
General Procedure for the Preparation of Lariat Ether Amines
113 and 114.
Compound 116 was isolated in 62% yield; ir (neat): ν 1745
-1
1
(C=O), 1147 (C-O) cm ; H nmr (deuteriochloroform): δ
1.13-1.19 (m, 24H), 1.77 (p, 2H), 2.83-2.87 (t, 2H, J = 6Hz), 3.49
(s, 4H), 3.65-4.29 (m, 19H), 6.66-6.95 (m, 6H).
To a solution of lariat ether nitrile 84 or 85 (2.50 mmoles) in
tetrahydrofuran (30 ml) under nitrogen, borane-methyl sulfide
complex (0.57 g, 7.50 mmoles) was added with a syringe
during a 10-minute period. The solution was stirred for
3 hours at room temperature for 84 and refluxed for 3 days for
85. The methyl sulfide was removed by distillation and the
liquid residue was stirred for 48 hours at room temperature.
After cooling to 0°, 6 N hydrochloric acid (15 ml) was added.
The solution was refluxed for 1 hour then cooled to 0° and
20% aqueous sodium hydroxide was added to pH 11. The
solution was extracted with dichloromethane (2 x 50 ml) and
the combined extracts were washed with 5% hydrochloric acid
(30 ml) and 10% aqueous sodium bicarbonate (30 ml) and
dried over magnesium sulfate. The solvent was evaporated in
vacuo to give a waxy solid that was used without further
purification.
Anal. Calcd. for C
H NO : C, 66.26; H, 8.49. Found: C,
38 57 10
66.38; H, 8.11.
General Procedure for the Preparation of Lariat Ether
Dicarboxylic Acids 80 and 81.
Under nitrogen at room temperature, lariat ether diester 115 or
116 (2.61 mmoles) was dissolved in 95% ethanol (30 ml). A
solution of 3 N potassium hydroxide (8.71 ml) was added and the
solution was stirred for 6 hours at room temperature. After
addition of 1 N hydrochloric acid (26.1 ml), the solution was
extracted with dichloromethane (3 x 30 ml). The combined
dichloromethane extracts were dried over magnesium sulfate and
evaporated in vacuo to give the desired product as an oil which
solidified on standing. Yields and physical, spectral and analysis
data for 80 and 81 are given in Table 8.

331
Synthesis of Lariat Ether Carboxylic Acids Based on Dibenzo-16-crown-5
Mar-Apr 2001
[17] T. Hayashita, J. H. Lee, J. C. Lee, J. Krzykawski and R. A.
Bartsch, Talanta, 39, 857 (1992).
Acknowledgements.
This work was supported by the Division of Chemical
Sciences of the Office of Basic Energy Science of the U.S.
Department of Energy (Grant DE-FG03-94ER14416 and earlier
contracts) and by a Howard Hughes Medical Institute grant
through the Undergraduate Biological Sciences Education
Program to Texas Tech University.
[18] T. Hayashita, J. H. Lee, M. G. Hankins, J. C. Lee, J. S. Kim, J.
M. Knobeloch and R. A. Bartsch, Anal. Chem., 64, 815 (1992).
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pp. 106 and 107.
[35] G. S. Heo, R. A. Bartsch, L. L. Schlobohm and J. G. Lee, J.
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[36] R. A. Bartsch, J. S. Kim, U. Olsher, D. W. Purkiss, V. Ramesh,
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