Synthesis of new proton-ionizable crown ether compounds containing substituted 1H-pyridin-4-one subcyclic units

Article abstract of DOI:10.1002/jhet.5570380604

Five novel pyridono-18-crown-6 (10-14) and two new benzyloxy-substituted pyridino-18-crown-6 (15 and 16) ligands have been prepared. By the catalytic hydrogenative removal of the benzyl group from the benzyloxy moiety at position 4 of the pyridine ring of

Full text of DOI:10.1002/jhet.5570380604

Nov-Dec 2001
Synthesis of New Proton-Ionizable Crown Ether Compounds
Containing Substituted 1H-Pyridin-4-one Subcyclic Units
Peter Huszthy*
1259
Research Group for Alkaloid Chemistry, Hungarian Academy of Sciences, H-1521 Budapest, Hungary
Julia Kertesz
Institute for Organic Chemistry, Budapest University of Technology and Economics, H-1521 Budapest, Hungary
Jerald S. Bradshaw and Reed M. Izatt
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA
J. Ty Redd
Department of Chemistry, Southern Utah University, Cedar City, UT 84720, USA
Received July 30, 2001
Five novel pyridono-18-crown-6 (10-14) and two new benzyloxy-substituted pyridino-18-crown-6 (15
and 16) ligands have been prepared. By the catalytic hydrogenative removal of the benzyl group from the
benzyloxy moiety at position 4 of the pyridine ring of 15 and 16, pyridono-18-crown-6 ethers 5 and 12 were
obtained. These ligands were transformed to their 3,5-dibromo (10 and 13) and 3,5-dinitro derivatives (11
and 14) by treatment with bromine in methylene chloride and nitric acid in acetic anhydride, respectively.
The latter proton-ionizable crown ethers have pK values of about 7.5 for 10 and 13 and 4.5 for 11 and 14.
a
Thus, they are good candidates for complexation and proton-coupled transport of selected cations.
J. Heterocyclic Chem., 38, 1259 (2001).
contradictory requirement is to engineer into the ionophore
a so-called "switching mechanism" which can create two
different binding states. These two states can be reversibly
interconverted by external forces such as redox, light, tem-
perature, and pH gradients. Macrocycles having a pH
switching mechanism have attracted the attention of many
researchers [1].
Introduction.
In order for an ionophore to perform optimum transport
across the membrane of an aqueous source phase-
lipophilic liquid membrane-aqueous receiving phase sys-
tem, it should possess a relatively high ion-binding ability
at the membrane phase-source phase interface, and have a
relatively low ion-binding ability at the membrane phase-
receiving phase interface. The solution for this seemingly
We are interested in crown ethers having a proton-ioniz-
able moiety as a part of the macroring. These ionophores

1260
P. Huszthy, J. Kertesz, J. S. Bradshaw, R. M. Izatt, and J. Ty Redd
Vol. 38
increase the cation-crown ether complex stability and
allow selective proton-coupled transport of metal ions
through various membrane systems without the need for
an anion to accompany the macrocycle-cation complex
[2]. Transport of the cations, in many cases, is pH depen-
dent so that transport can be turned on and off by adjusting
the pH [1,2b,3]. We have used water-insoluble proton-ion-
izable macrocycles containing the 1H-pyridin-4-one (1)
(see Figure 1) and 1H-pyridin-4-thione (2) subcyclic units,
such as 6, 7, and 9, as carriers in the transport of metal ions
in a H O-CH Cl -H O liquid membrane system [2b,2c,4].
2
2
2
2
The proton-ionizable macrocyclic carriers should have
lipophilic substituents to insure that they remain in the
organic membrane. Without a lipophilic side chain, no
transport occurred, because the crown ether distributed
into the aqueous phase so that it was not available as a car-
rier [2c]. In the case of pyridono ligands 6 and 7, transport
of alkali metal ions was observed for source phase pH val-
ues higher than 12, and in the case of thiopyridono ligand 9
and 12 was also obtained by the catalytic hydrogenation of
pyridino macrocycle 16 in an excellent yield. Bromination
of ligands 5 and 12 was carried out in dichloromethane at
room temperature using a large excess of bromine. The
yields of dibromo-substituted pyridono-crown ethers 10
and 13 were good to moderate (63% and 39%, respec-
tively), although the same reaction conditions were used in
both cases. Crude dibromo derivative 10 could be purified
by crystallization, but the purification of 13 required chro-
matography. Nitration of pyridonocrown ethers 5 and 12
to form dinitro derivatives 11 and 14 was performed in a
mixture of 100% nitric acid and acetic anhydride and
required heat. The yields were low (30% for 11 and 25%
for 14) and chromatography was needed to purify the solid
products. We plan to further investigate these reactions in
order to obtain better yields for both bromination and
nitration of the pyridonocrown ethers.
higher than 10 [2c]. Since the pK values for removal of a
a
proton from octyl-substituted 6 and 7 are presumably close
to that for 4-pyridone 1 (11.09) [5] or non-alkyl-substi-
tuted 5 (10.98) [6] and the pK value for 9 is close to that
a
for 8 (8.65) [7] or 2 (8.3) [8], respectively, transport can
only take place when an appreciable amount of the macro-
cycle in question is ionized at the source phase-organic
phase interface [2b,2c].
We have long wanted to prepare proton-ionizable
macrocyclic ligands with pK values that would allow the
a
transport of cations at relatively low source phase pH val-
ues. These more acidic pH-switched ligands would also be
used to transport some of the heavy metal cations and
ammonium and organic primary ammonium ions at rela-
tively low source phase pH values [2c]. Since 3,5-
dibromo-1H-pyridin-4-one (3) and 3,5-dinitro-1H-pyridin-
Benzyloxy-substituted pyridinocrown ether 15 was pre-
pared using a Williamson ether synthesis by treating the
disodium salt of 4-benzyloxy-2,6-pyridinedimethanol (18)
[12] with tetraethylene glycol ditosylate (19) [13] to give a
47% yield (Scheme 2). When 4-benzyloxy-2,6-
pyridinedimethanol ditosylate (21) [14] and tetraethylene
4-one (4) have pK values of 7.73 [9] and 4.56 ]10],
a
respectively, new non-lipophilic proton-ionizable ligands
10 and 11 containing these substituted pyridone subcyclic
units (Figure 1) and their lipophilic tetrahexyl-substituted
analogues 13 and 14 have been prepared for future proton-
coupled cation transport studies. The preparation of new
lipophilic macrocycle 12 and its known non-lipophilic
analogue 5 [6] by a new straightforward method is also
reported. A report of the cation transport properties of
these interesting new proton-ionizable macrocycles will be
published when that work is finished.
Scheme 2
Results and Discussion.
The known pyridonocrown ether 5 [6] was obtained
from the corresponding benzyloxy-substituted
pyridinocrown ether 15 instead of from its tetrahydropy-
ranyloxy analogue (Scheme 1). The benzyl protecting
group is better than the THP protecting group for these
kinds of syntheses [11]. The novel lipophilic pyridono lig-

Nov-Dec 2001
Synthesis of New Proton-Ionizable Crown Ether Compounds
1261
EXPERIMENTAL
Infrared spectra were recorded on a Zeiss Specord IR 75 spec-
glycol were used in similar reaction conditions, a very low
yield of crown ether 15 was obtained. (The latter reaction
is not shown.) However, a good yield (49%) of 16 was
obtained when ditosylate 21 was treated with the disodium
salt of tetrahexyl-substituted tetraethylene glycol 20 under
the above mentioned reaction conditions (Scheme 2). We
presume that the solubility of the appropriate disodium salt
in tetrahydrofuran plays an important role in this type of
cyclization reaction.
1
13
trometer. H (500 MHz) and C (125 MHz) nmr spectra were
taken on a Bruker DRX-500 Avance spectrometer in deuteri-
ochloroform unless otherwise indicated. Molecular weights were
determined by a Perkin Elmer SIEX API 2000 triplequad mass
spectrometer. Elemental analyses were performed in the
Microanalytical Laboratory of the Department of Organic
Chemistry, L. Eötvös University, Budapest, Hungary. Melting
points were taken on a Boetius micro melting point apparatus and
were uncorrected. Starting materials were purchased from
Aldrich Chemical Company unless otherwise noted. Silica gel 60
In our previous studies of cation transport by lipophilic
proton-ionizable crown ethers [2b,2c,4], a single long
chain alkyl substituent was used to effect lipophilicity to
the macrocycle (6, 7, and 9, for example). Using only one
alkyl substituent creates a stereogenic center and could
lead to complications in some complexation studies.
Having only one long chain alkyl side arm causes the lig-
and to be surface active and results in foaming during the
transport experiments. The four shorter hexyl arms secure
lipophilicity for the ligand without causing foaming.
Therefore, we have synthesized symmetric tetrahexyl-sub-
stituted crown ethers 12-14 and 16. Preparation of tetra-
hexyl-substituted tetraethylene glycol 20 needed to pre-
pare crown ether 16 was accomplished from the reported
methyl benzyloxyacetate (22) [15] as shown in Scheme 3.
Ester 22 was treated with an excess of hexylmagnesium
bromide in a mixture of ether and benzene. When ester 22
in benzene was added to the ethereal Grignard reagent, a
higher yield of 23 (95%) was obtained than when using
only ether as a solvent. Dibenzyl-protected tetraethylene
glycol 24 was obtained using the Williamson ether synthe-
sis by treating alcohol 23 with diethylene glycol ditosylate
(17). In this case, the yield was low (32%) probably the
result of an unfavorable steric effect of the tertiary alcohol
portion of 23. Removal of the benzyl-protecting groups
from 24 by catalytic hydrogenation went smoothly giving
a good yield (94%) of tetrahexyl-substituted tetraethylene
glycol 20.
F
(Merck) and aluminum oxide 60 F
neutral type E
254
254
(Merck) plates were used for tlc. Aluminum oxide (neutral, acti-
vated, Brockman I) and silica gel 60 (70-200 mesh, Merck) were
used for column chromatography. Solvents were dried and puri-
fied according to well established methods [16]. Evaporations
were carried out under reduced pressure unless otherwise stated.
3,6,9,12,15-Pentaoxa-21-azabicyclo[15.3.1]heneicosa-17,20-
diene-19(21H)-one (5) (Scheme 1).
To 4.21 g (10 mmole) of benzyloxypyridinocrown ether mono-
hydrate 15 was added under argon 0.4 g of 10% palladium on char-
coal catalyst and then 280 ml of ethanol. The mixture was stirred
under argon for 2 minutes, and then the argon was replaced by
hydrogen and hydrogenation was carried out in the usual way at
room temperature and at atmospheric pressure to give pyri-
donocrown ether 5 (3.25 g, 98%) which was purified by recrystal-
lization from acetone to give white crystals of pure 5 (2.55 g, 77%)
as a monohydrate identical in every aspect to that reported [6].
18,20-Dibromo-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]-
heneicosa-17,20-diene-19(21H)-one (10) (Scheme 1).
To a stirred solution of pyridonocrown ether monohydrate 5
(166 mg, 0.5 mmole) in 10 ml of dichloromethane was added drop-
wise at room temperature a solution of bromine (1.02 ml, 3.3 g, 21
mmole) in 10 ml of dichloromethane. The reaction mixture was
stirred at room temperature until the starting material disappeared
according to tlc analysis (about 4 hours). After the reaction was
completed, dichloromethane (10 ml) and aqueous triethylammo-
nium acetate (30 ml of 1 M solution) was added. The phases were
shaken well, and separated. The organic phase was shaken with 20
ml of water, dried over anhydrous magnesium sulfate, filtered, and
the solvent was removed. The residue was purified by recrystal-
lization from methanol to give 143 mg (63%) of 10 as white crys-
tals; mp 170-171°; R = 0.55 (silica gel tlc, 11% MeOH in
f
CH Cl ); ir (potassium bromide): 3328, 3024, 2872, 1608, 1584,
2
2
1572, 1516, 1504, 1468, 1432, 1348, 1288, 1264, 1248, 1104,
–1
1
1088, 1064, 1056, 1048, 1008, 984, 940, 848, 712, 680 cm ; H
nmr: δ 3.67 (s, 8H), 3.79 (s, 8H), 4.58 (s, 4H), 10.4 (broad s, 1H,
H
pyridone NH proton, shifted considerably by changing the temper-
13
ature); C nmr: δ 68.66, 70.11, 70.87, 70.91, 71.67, 109.27,
c
+
143.27, 168.28; ms: (electrospray) 472 (M+1) .
Anal. Calcd. for C H Br NO (471.142): C, 38.24; H, 4.49;
15 21
2
6
N, 2.97; Br, 33.92. Found: C, 37.96; H, 4.75; N, 3.14; Br, 33.66.
18,20-Dinitro-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]hene-
icosa-17,20-diene-19(21H)-one (11) (Scheme 1).
To pyridonocrown ether monohydrate 5, (331 mg, 1 mmole)
was added a mixture made previously from fuming nitric acid

1262
P. Huszthy, J. Kertesz, J. S. Bradshaw, R. M. Izatt, and J. Ty Redd
Vol. 38
(0.66 g, 10.5 mmole, 100% HNO , specific gravity, 1.52) and
Macrocycle 14 was prepared as above for 11 from 12 (325 mg,
0.5 mmole) using 0.33 g (5.3 mmole) of 100% nitric acid and 10
ml of acetic anhydride. The crude product was purified by
preparative layer chromatography on silica gel using 5%
methanol in dichloromethane as eluent to give 14 (98 mg, 25%)
3
acetic anhydride (20 ml, 21.64 g, 212 mole) at room temperature.
The reaction mixture was stirred at room temperature for 10 min-
utes then the temperature was raised to 60° and sustained until the
starting material disappeared according to tlc analysis (about 3
hours). The volatile materials were removed and the residue was
purified by preparative layer chromatography on silica gel (Merck
as a yellow solid; mp 133-135°; R = 0.45 (silica gel tlc, 5%
f
MeOH in CH Cl ); ir (potassium bromide): 3436, 2931, 2859,
2
2
PLC plates 60F , 0.5 mm silica gel thickness, Art number:
1620, 1522, 1468, 1357, 1330, 1261, 1222, 1135, 1117, 1082,
254
-1
1
1.05744) using 11% methanol in dichloromethane as eluent to give
138 mg (30%) of pure 11 as a yellow solid; mp > 360° (methanol);
R = 0.48 (silica gel tlc, 11% MeOH in CH Cl ); ir (potassium bro-
1025, 955, 829, 801 cm ; H nmr: δ 0.89 (tr, J = 7 Hz, 12H),
H
1.26-1.29 (m, 32H), 1.50-1.53 (m, 8H), 3.54 (s, 4H), 3.66-3.67
13
(m, 4H), 3.69-3.70 (m, 4H), 4.56 (s, 4H); C nmr: δ 14.29,
f
2
2
C
mide): 3440, 3048, 2912, 1616, 1564, 1500, 1488, 1464, 1364,
1256, 1216, 1128, 1100, 1088, 1040, 952, 904, 824 cm ; H nmr
22.84, 23.39, 29.92, 30.06, 32.08, 59.17, 70.03, 71.11, 71.68,
78.91, 138.49, 152.77, 161.82; ms: (electrospray) 741 (M+1) .
-1
1
+
(DMSO-d ): δ 3.31 (2H, H O), 3.56 (s, 8H), 3.58 (s, 8H), 4.41 (s,
Anal .Calcd for C H N O •2H O (776.019): C, 60.36; H,
9.48; N, 5.41. Found: C, 60.14; H, 9.42; N, 5.17.
6
H
2
39 69
3
10
2
13
4H); C nmr (DMSO-d ): δ 69.37, 69.66, 69.71, 69.76, 69.81,
6
C
+
142.28, 149.62, 159.78; ms: (electrospray) 404 (M+1) .
Anal. Calcd for C H N O •H O (421.36): C, 42.76; H,
19-Benzyloxy-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]hene-
icosa-1(21),17,19-triene (15) (Scheme 2).
15 21
3
10
2
5.50; N, 9.97. Found: C, 42.55; H, 5.52; N, 9.88.
To a well stirred suspension of sodium hydride (0.63 g, 21
mmole, 80% dispersion in mineral oil) in 5 ml of pure and dry
tetrahydrofuran was added dropwise at 0° under argon a solution
of 4-benzyloxy-2,6-pyridinedimethanol (18, 1.6 g, 6.52 mmole)
in 30 ml of pure and dry tetrahydrofuran. After the addition was
complete, the mixture was stirred at 0° for 10 minutes, at room
temperature for 30 minutes and then at reflux temperature for 4
hours. The mixture was cooled to -60°, and a solution of tetraeth-
ylene glycol ditosylate (19, 3.5 g, 7 mmole) in 30 ml of pure and
dry tetrahydrofuran was added. The mixture was stirred at -60°
for 20 minutes and at room temperature for 5 days. The solvent
was removed, and the residue was dissolved in a mixture of
dichloromethane (100 ml) and ice cold water (50 ml). Phases
were mixed and separated, and the aqueous phase was extracted
with dichloromethane (3x50 ml). The combined organic phase
was dried over anhydrous magnesium sulfate and filtered, and the
solvent was removed. The residue was purified by column chro-
matography on alumina using 1% ethanol in toluene as eluent to
5,5,13,13-Tetrahexyl-3,6,9,12,15-pentaoxa-21-azabicy-
clo[15.3.1]heneicosa-17,20-diene-19(21H)-one (12) (Scheme 1).
Macrocycle 12 was prepared as above for 5 from 16 (3.7 g, 5
mmole) using 0.2 g of 10% palladium on charcoal catalyst and
140 ml of ethanol as solvent. The crude product was purified by
column chromatography on alumina using 2% ethanol in toluene
as eluent to give 12 (3.5 g, 94%) as a colorless oil; R = 0.48 (sil-
f
ica gel tlc, 9% MeOH in CH Cl ); ir (neat): 3516, 3267, 3063,
2
2
2930, 2860, 1634, 1584, 1531, 1455, 1377, 1103, 1026, 982, 965,
-1 1
866, 727 cm ; H nmr: δ 0.86 (tr, J = 7 Hz, 12H), 1.19-1.27 (m,
H
32H), 1.42-1.58 (m, 8H), 3.43 (s, 4H), 3.48-3.49 (m, 4H), 3.60-
3,61 (m, 4H), 4.37 (s, 4H), 6.19 (s, 2H), 11.48 (broad s, 1H, pyri-
done NH proton, shifted considerably by changing the tempera-
13
ture); C nmr: δ 14.20, 22.75, 23.47, 30.01, 31.87, 32.86,
C
61.06, 70.10, 71.31, 73.41, 79.81, 115.07, 147.29, 180.54; ms:
+
(electrospray) 651 (M+1) .
Anal .Calcd for C H NO (649.993): C, 72.07; H, 11.01; N,
39 71
6
2.15. Found: C, 71.93; H, 11.27; N, 2.09.
give 1.23 g (47%) of 15 as a colorless oil; R = 0.65 (alumina tlc,
f
5% MeOH in CH Cl ); ir (neat): 3548, 3373, 3064, 3034, 2869,
19,20-Dibromo-5,5,13,13-tetrahexyl-3,6,9,12,15- pentaoxa-21-
azabicyclo[15.3.1]heneicosa-17,20-diene-19(21H)-one (13)
(Scheme 1).
2
2
1599, 1575, 1498, 1454, 1356, 1327, 1250, 1113, 1028, 990, 948,
–1
1
861, 740, 699 cm ; H nmr: δ 3.02 (broad s, 2H, H O) 3.55-
H
2
3.58 (m, 8H), 3.63-3.66 (m, 4H), 3.70-3.72 (m, 4H), 4.67 (s, 4H),
Macrocycle 13 was prepared as above for 10 from 12 (325 mg,
0.5 mmole) dissolved in 10 ml of dichloromethane using a solu-
tion of bromine (1.02 ml, 3.2 g, 21 mmole) in 10 ml of
dichloromethane. The crude product was purified by preparative
layer chromatography on silica gel using 2.4% methanol in
13
5.10 (s, 2H), 6.85 (s, 2H), 7.31-7.40 (m, 5H); C nmr: δ 69.63,
c
69.90, 70.49, 70.68, 71.05, 73.75, 107.62, 127.62, 128.38,
+
128.78, 135.91, 159.86, 166.00; ms: (electrospray) 404 (M+1) .
Anal. Calcd. for C H NO •H O (421.49): C, 62.69; H, 7.41;
22 29
6
2
N, 3.32. Found: C, 62.44; H, 7.26; N, 3.14.
dichloromethane as eluent to give 13 (139 mg, 34%) as an oil; R
f
= 0.70 (silica gel tlc, 2.4% MeOH in CH Cl ); ir (neat): 3324,
19-Benzyloxy-5,5,13,13-tetrahexyl-3,6,9,12,15-pentaoxa-21-
2
2
2955, 2931, 2859, 1606, 1576, 1466, 1378, 1352, 1262, 1216,
azabicyclo[15.3.1]heneicosa-1(21),17,19-triene (16) (Scheme 2).
-1
1
1120, 1069, 800, 758 cm ; H nmr: δ 0.88 (tr, J = 7 Hz, 12H),
H
To a well stirred suspension of sodium hydride (0.32 g, 10.7
mmole, 80% dispersion in mineral oil) in 3 ml of pure and dry
tetrahydrofuran was added dropwise at 0° under argon a solution
of tetraethylene glycol 20 (1.75 g, 3.3 mmole) in 15 ml of pure
and dry tetrahydrofuran. After the addition was completed, the
mixture was stirred at 0° for 10 minutes, at room temperature for
30 minutes and then at reflux temperature for 4 hours. The mix-
ture was cooled to –60°, and a solution of 4-benzyloxy-2,6-
pyridinedimethanol ditosylate (21, 2.0 g, 3.6 mmole) in 15 ml of
pure and dry tetrahydrofuran was added. The mixture was stirred
at – 60° for 30 minutes and at room temperature for three days.
The solvent was removed, and the residue was dissolved in a
1.23-1.29 (m, 32H), 1.47-1.55 (m, 8H), 3.49 (s, 4H), 3.54-3.56
(m, 4H), 3.64-3.65 (m, 4H), 4.53 (s, 4H), 9.97 (broad s, 1H, pyri-
done NH proton, shifted considerably by changing the tempera-
13
ture); C nmr: δ 14.22, 22.77, 25.28, 29.68, 31.31, 31.76,
C
61.63, 69.49, 74.18, 75.68, 78.08, 110.51, 143.16, 168.58; ms:
+
(electrospray) 808 (M+1) .
Anal. Calcd for C H Br NO (806.785): C, 58.06; H, 8.62;
39 69
2
6
Br, 19.68, N, 1.74. Found: C, 57.82; H, 8.47; Br, 19.52; N, 1.68.
18,20-Dinitro-5,5,13,13-tetrahexyl-3,6,9,12,15-pentaoxa-21-
azabicyclo[15.3.1]heneicosa-17,20-diene-19(21H)-one (14)
(Scheme 1).

Nov-Dec 2001
Synthesis of New Proton-Ionizable Crown Ether Compounds
1263
mixture of dichloromethane (60 ml) and ice cold water (30 ml).
Phases were shaken well and separated, and the aqueous phase
was extracted with dichloromethane (3x30 ml). The combined
organic phase was dried over anhydrous magnesium sulfate, fil-
tered, and the solvent was removed. The residue was purified by
column chromatography on alumina using 0.4% ethanol in
After the addition was complete, the mixture was stirred at 0° for
10 minutes, at room temperature for 30 minutes and then at reflux
temperature for 4 hours. The mixture was cooled to room tempera-
ture, and solid diethylene glycol ditosylate 17 (4.58 g, 11.1 mmole)
was added in one portion. The mixture was stirred at room tem-
perature for 20 minutes and at reflux temperature for 3 days. By
that time the tlc analysis showed the total consumption of 17 and a
large amount of unreacted 23. The mixture was cooled to room
temperature, and solid diethylene glycol ditosylate 17 (1.0 g, 4.8
mmole) was again added in one portion. Stirring was continued at
room temperature for 20 minutes and then at reflux temperature for
2 days. The solvent was removed, and the residue was dissolved in
a mixture of ether (300 ml) and ice cold water (250 ml). Phases
were shaken well and separated, and the aqueous phase was
extracted with ether (3x100 ml). The combined organic phase was
dried over anhydrous magnesium sulfate and filtered, and the sol-
vent was removed. The residue was purified by column chro-
matography on silica gel using 0.5% methanol in dichloromethane
toluene as eluent to give 16 (1.2g, 49%) as a colorless oil; R =
f
0.55 (alumina tlc, 2% EtOH in toluene); ir (neat): 3030, 2928,
2870, 1600, 1544, 1456, 1368, 1328, 1104, 1052, 848, 736, 696
–1
1
cm ; H nmr: δ 0.88 (tr, J = 7 Hz, 12H), 1.19-1.27 (m, 32H),
H
1.43-1.515 (m, 8H), 3.43 (s, 4H), 3.45 (tr, J = 5 Hz, 4H), 3.52 (tr,
J = 5 Hz, 4H), 4.66 (s, 4H), 5.11 (s, 2H), 6.87 (s, 2H), 7.33-7.43
13
(m, 5H); C nmr: δ 14.11, 22.70, 23.10, 29.99, 31.86, 33.01,
C
60.55, 69.82, 70.93, 72.20, 74.05, 78.96, 107.56, 127.62, 128.36,
+
128.71, 135.84, 159.96, 165.90; ms: (electrospray) 741 (M+1) .
Anal Calcd. for C H NO (740.117): C, 74.65; H, 10.49; N,
46 77
6
1.89. Found: C, 74.48; H, 10.62; N, 1.73.
2,2,8,8-Tetrahexyl-3,6,9-trioxaundecane-1,11-diol (20) (Scheme 3).
as eluent to give 2.8. g (32%) of 24 as a colorless oil; R = 0.25 (sil-
f
ica gel tlc, 0.5% MeOH in CH Cl ); ir (neat): 3064, 3048, 3032,
Compound 20 was prepared as above for 5 from 24 (3.56 g, 5
mmole) using 0.2 g of 10% palladium on charcoal catalyst and
140 ml of ethanol. The crude product was purified by column
chromatography on silica gel using 8% acetone in cyclohexane as
2
2
–1
2928, 2888, 2864, 1492, 1456, 1372, 1208, 1104, 736, 696 cm ;
1
H nmr: δ 0.90 (tr, J = 7 Hz, 12H), 1.21-1.32 (m, 32H), 1.47-1.52
H
(m, 8H), 3.33 (s, 4H), 3.49 (tr, J = 7Hz, 4H), 3.59 (tr, J = 7Hz, 4H),
13
4.51 (s, 4H), 7.33-7.34 (m, 10H); C nmr: δ 14.09, 22.66, 22.77,
eluent to give 20 (2.5 g, 94%) as a colorless oil; R = 0.10 (silica
C
f
29.88, 31.84, 33.24, 60.44, 71.01, 71.98, 73.21, 78.35, 127.44,
127.61, 128.23, 138.62.
gel tlc, 0.5% MeOH in CH Cl ); ir (neat): 3432, 2928, 2888,
2
2
–1
1
2864, 1464, 1376, 1248, 1084, 940, 724 cm ; H nmr: δ 0.87
H
(tr, J = 7 Hz, 12H), 1.20-1.26 (m, 32H), 1.33-1.51 (m, 8H), 3.41
(s, 4H), 3.49-3.50 (m, 4H), 3.58-3.59 (m, 4H), 4.16 (broad s, 2H,
Acknowledgements.
Financial support by the Hungarian Scientific Research Fund
(OTKA T-25071) and the Office of Naval Research (USA) is
greatfully acknowledged.
hydroxyl protons, shifted considerably by changing the tempera-
13
ture); C nmr: δ 14.01, 22.66, 23.31, 29.96, 31.81, 32.24,
C
59.86, 63.26, 71.17, 80.06.
7-Benzyloxymethyl-tridecane-7-ol (23) (Scheme 3).
REFERENCES AND NOTES
To a well stirred solution of ethereal hexylmagnesium bro-
mide, prepared from magnesium metal (14.6 g, 0.6 mole), hexyl
bromide (99.05 g, 0.6 mole) and 350 ml of pure and dry ether,
was added dropwise under argon a solution of methyl benzyloxy-
acetate (27.03 g, 0.15 mole) in 175 ml of pure and dry benzene.
After the addition was completed, the reaction mixture was
stirred at reflux temperature for 14 hours. The reaction mixture
was cooled and first 1 liter of benzene and then 1 liter of saturated
aqueous ammonium chloride solution were added. The mixture
was transferred to a separatory funnel and mixed well. The aque-
ous phase was extracted twice with 500 ml portions of benzene.
The combined organic phase was dried over magnesium sulfate,
filtered, and the solvent was removed. The residue was purified
by fractional distillation under reduced pressure to give 45.7 g
(95%) of pure 23 as a colorless oil, bp 138-140° (0.2 mmHg);
*
For correspondence: email huszthy.szk@chem.bme.hu,
phone 36-1-4632111, fax 36-1-4633297.
[1] C. W. McDaniel, J. S. Bradshaw, and R. M. Izatt,
Heterocycles, 30, 665 (1990).
[2a] E. Kimura, C. A. Dalimunte, A. Yamashita, and R.
Machida, J. Chem. Soc., Chem. Commun., 294 (1985); [b] R. M.
Izatt, G. C. LindH, G. A. Clark, Y. Nakatsuji, J. S. Bradshaw, J. D.
Lamb, and J. J. Christensen, J. Memb. Sci., 31, 1 (1987); [c] J. S.
Bradshaw, R. M. Izatt, P. Huszthy, Y. Nakatsuji, J. F. Biernat, H.
Koyama, C. W. McDaniel, S. G. Wood, R. B. Nielson, G. C. LindH,
R. L. Bruening, J. D. Lamb, and J. J. Christensen, In Physical
Organic Chemistry 1986, H. Kobayashi, Editor, Elsevier Science
Publishers, Amsterdam, The Netherlands, pp 553-560, 1986; [d] J.
T. Redd, J. S. Bradshaw, P. Huszthy, R. M. Izatt, and N. K. Dalley, J.
Heterocyclic Chem. 35, 1 (1998).
[3] C. A. Chang, J. Twu, and R. A. Bartsch, Inorg. Chem., 25,
396 (1986).
[4] R. M. Izatt, G. C. LindH, R. L. Bruening, P, Huszthy, J. D.
Lamb, J. S. Bradshaw, and J. J. Christensen, J. Incl. Phenom., 5, 739
(1987).
[5] J. J. Christensen, L. D. Hansen, and R. M. Izatt, Handbook
of Proton Ionization, Heats and Related Thermodynamic Quantities,
Wiley-Interscience, New York, NY, 1976.
[6a] Y. Nakatsuji, J. S. Bradshaw, P.-K. Tse, G. Arena, B. E.
Wilson, N. K. Dalley, and R. M. Izatt, J. Chem. Soc., Chem.
Commun., 749 (1985); [b] J. S. Bradshaw, Y. Nakatsuji, P. Huszthy,
B. E. Wilson, N. K. Dalley, and R. M. Izatt, J. Heterocyclic Chem.,
23, 353 (1986).
R = 0.55 (silica gel tlc, 0.5% MeOH in CH Cl ); ir (neat): 3464,
f
2
2
-1
1
3032, 2928, 2856, 1456, 1376, 1100, 736, 696 cm ; H nmr: δ
H
0.92 (tr, J = 7 Hz, 6H), 1.30-1.34 (m, 16H), 1.51 (tr, J = 7 Hz,
4H), 2.24 (broad s, 1H), 3.35 (s, 2H), 4.57 (s, 2H), 7.30-7.39 (m,
13
5H); C nmr: δ 14.25, 22.79, 23.53, 30.12, 31.98, 36.69, 73.54,
c
74.10, 75.81, 127.74, 127.78, 128.51, 138.46.
7,15-Bis(benzyloxymethyl)-7,15-dihexyl-8,11,14-trioxahene-
icosane (24) (Scheme 3).
To a well stirred suspension of sodium hydride (3 g, 100 mmole,
80% dispersion in mineral oil) in 30 ml of pure and dry tetrahydro-
furan was added dropwise at 0° under argon a solution of alcohol
23 (7.88 g, 24.6 mmole) in 200 ml of pure and dry tetrahydrofuran.

1264
P. Huszthy, J. Kertesz, J. S. Bradshaw, R. M. Izatt, and J. Ty Redd
Vol. 38
[7] J. S. Bradshaw, P. Huszthy, H. Koyama, S. G. Wood, S. A.
[13] P. Huszthy, E. Samu, B. Vermes, G. Mezey-Vandor, M.
Nogradi, J. S. Bradshaw, and R. M. Izatt, Tetrahedron, 55, 1491
(1999).
[14] G. Horvath, C. Rusa, Z. Kontos, J. Gerencser, and P.
Huszthy, Synth. Commun., 29, 3719 (1999).
[15] T. Mukaiyama, I. Shiina, H. Iwadare, M. Saitoh, T.
Nishimura, N. Ohkawa, H. Sakoh, K. Nishimura, Y. Tam, M.
Hasegawa, K. Yamada, and K. Saitoh, Chem. Europ. J., 5, 121
(1999).
Strobel, R. B. Davidson, R. M. Izatt, N. K. Dalley, J. D. Lamb, and J.
J. Christensen, J. Heterocyclic Chem., 23, 1837 (1986).
[8] A. Albert and G. B. Barlin, J. Chem. Soc., 2384 (1959).
[9] J. W. Bunting. A. Toth, C. K. M. Heo, and R. G. Moors, J.
Am. Chem. Soc., 112, 8878 (1990).
[10] A. Gordon, A. R. Katritzky, and S. K. Roy, J. Chem. Soc.
(B), 556 (1968).
[11] G. Horvath and P. Huszthy, Tetrahedron Asymmetry, 10,
4573 (1999).
[16] J. A. Riddick and W. B. Burger, Organic Solvents In
rd
[12] G. Chessa and A. Scrivanti, J. Heterocyclic Chem., 34,
1851 (1997).
Techniques of Organic Chemistry, 3 ed.; A. Weissberg, Editor;
Wiley-Interscience: New York, 1970; Vol. II.