Synthesis of new N-pivot lariat crown ethers containing a propylene linkage in the side arm

Article abstract of DOI:10.1021/jo961098w

A series of new 15- and 18-membered N-pivot lariat aza-crown ethers having a propylene linkage in the side arm was prepared starting from functionalized diethanolamines and functionalized lariat aza-crown ethers containing the easily modified benzotriazole moiety. Addition reactions of such derivatives to electron-rich vinyl ethers or vinylamides followed by displacement of the benzotriazolyl group in the addition products by hydrogen (by reduction with LiAlH₄) gives a variety of N-(3-oxo-3-substituted)- and N-(3-aza-3-substituted)propylene side-armed derivatives of aza-crown ethers. Stability constants for the complexes of several synthesized lariats with metal cations are discussed.

Full text of DOI:10.1021/jo961098w

7578
J . Org. Chem. 1996, 61, 7578-7584
Syn th esis of New N-P ivot La r ia t Cr ow n Eth er s Con ta in in g a
P r op ylen e Lin k a ge in th e Sid e Ar m
Alan R. Katritzky,* Olga V. Denisko, and Sergei A. Belyakov
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Otto F. Schall and George W. Gokel
Department of Molecular Biology and Pharmacology, Washington University School of Medicine,
Washington University, St. Louis, Missouri 63110
Received J une 11, 1996X
A series of new 15- and 18-membered N-pivot lariat aza-crown ethers having a propylene linkage
in the side arm was prepared starting from functionalized diethanolamines and functionalized lariat
aza-crown ethers containing the easily modified benzotriazole moiety. Addition reactions of such
derivatives to electron-rich vinyl ethers or vinylamides followed by displacement of the benzotriazolyl
group in the addition products by hydrogen (by reduction with LiAlH4) gives a variety of N-(3-oxo-
3-substituted)- and N-(3-aza-3-substituted)propylene side-armed derivatives of aza-crown ethers.
Stability constants for the complexes of several synthesized lariats with metal cations are discussed.
In tr od u ction
arms substituted by donor groups in the o-position of the
phenyl ring have demonstrated improved complexing
ability and selectivity3,6-11 compared to the unsubstituted
(benzyl) side arm. This phenomenon in the case of
phenolic side-armed N-pivot crowns is satisfactorily
explained by the “loose/normal/rigid ligand” approach,7,8
based on CPK space-filling models: when an ideal
6-membered chelate ring is formed, the cation trapped
in the crown cavity is effectively capped apically by the
oxygen anion from the o-hydroxybenzyl side arm. In this
most successful case, a “normal” 6-membered chelate is
formed by the metal cation, one nitrogen, three carbon
atoms (one of the methylene group and two of the phenyl
ring), and one oxygen, while in two other cases, “loose”
(7-membered ring) and “rigid” (5-membered ring), che-
lates have less than optimal geometries and correspond-
ingly poorer selectivity and stability of their complexes.
In the case when an ammonium cation is accommodated
by the lariat N-pivot crown [N-(2-methoxyethyl)aza-18-
crown-6], NH4+ binds to donor atoms of the ring by means
of three discrete hydrogen bonds in a tetrahedral manner,
but it is not capped from the apical direction by the side
arm: the chain of two carbons and one oxygen is too short
to allow such an interaction of the last N-H bond in the
perpendicular direction.3 Complete hydrogen bonding of
The intensive development of the lariat crown ether
concept1 led to the synthesis of hundreds of side-armed
crown ethers, designed for uses ranging from routine
(polymer-supported PTC catalysts, separation/extraction
reagents, etc.) to sophisticated (applications as redox
switches for membrane transport, synthetic cation-
conducting channels, nucleotide-based molecular boxes,
etc.).2 The concept of mimicking the cation-binding
behavior of naturally occurring ionophores, such as
valinomycin, spurred efforts culminating in the syntheses
of both C- and N-pivot lariat ethers.3 The former proved
to be the more rigid; inversion of the nitrogen atom at
the N-pivot ethers allows more freedom for the side arm
to effectively participate in coordination and leads to
higher cation-binding affinities.4 Another advantage of
the N-pivot lariats is their easier synthetic accessibility,
frequently based on chemical modification of the parent
NH-containing azacrowns.5 Investigations in the area
of the synthesis and especially of applications of N-pivot
lariat crown ethers are now expanding dramatically, as
reflected by the continuously growing number of publica-
tions.
Several trends in the design of N-containing lariat
ethers are based on structural and synthetic consider-
ations. For example, for a side arm attached to a N-atom,
molecular modeling predicted that an optimal distance
for the interaction between a cation bound to the mac-
rocyclic ring and a donor group covering a cation from
the apical direction is three carbon atoms.2 Indeed,
various N-pivot aza-crown lariats containing benzyl side
+
the NH4 cation was attained only when an extra
oxyethylene unit was introduced into the side arm; with
the 2′-(2-methoxyethoxy)ethyl substituent only the re-
mote oxygen was involved in binding. These factors
prompted us to design and synthesize a new series of
N-pivot lariat crown ethers containing a propylene unit
between the nitrogen atom of the ring and the side-arm
donor.
X Abstract published in Advance ACS Abstracts, October 1, 1996.
(1) Gokel, G. W.; Dishong, D. M.; Diamond, C. J . J . Chem. Soc.,
Chem. Commun. 1980, 1053.
(2) Gokel, G. W. Chem. Soc. Rev. 1992, 39.
(3) Schultz, R. A.; White, B. D.; Dishong, D. M.; Arnold, K. A.; Gokel,
G. W. J . Am. Chem. Soc. 1985, 107, 6659.
(6) Dix, J . P.; Vo¨gtle, F. Chem. Ber. 1980, 113, 457.
(7) Katayama, Y.; Nita, K.; Ueda, M.; Nakamura, H.; Takagi, M.;
Ueno, K. Anal. Chim. Acta 1985, 173, 193.
(4) Gokel, G. W.; Arnold, K. A.; Cleary, T.; Friese, R.; Gatto, V.; Goli,
D.; Hanlon, C.; Kim, M.; Miller, S.; Ouchi, M.; Posey, I.; Sandler, A.;
Viscariello, A.; White, B.; Wolfe, J .; Yoo, H. In ACS Symposium Series,
326: Phase-Transfer CatalysissNew Chemistry, Catalysts, and Ap-
plications; Starks, C. M., Ed.; ACS: Washington, DC, 1987; p 24.
(5) Gokel, G. W.; Nakano, A. In Crown Compounds: Towards Future
Applications; Cooper, S. R., Ed.; VCH Publishers: New York, 1992;
pp 1-27.
(8) Katayama, Y.; Fukuda, R.; Takagi, M. Anal. Chim. Acta 1986,
185, 295.
(9) Vo¨gtle, F.; Knops, P. Angew. Chem., Int. Ed. Engl. 1991, 30, 958.
(10) Lukyanenko, N. G.; Pastushok, V. N.; Bordunov, A. V. Synthesis
1991, 241.
(11) Lukyanenko, N. G.; Pastushok, V. N.; Bordunov, A. V.; Vetrogon,
V. I.; Vetrogon, N. I.; Bradshaw, J . S. J . Chem. Soc., Perkin Trans. 1
1994, 1489.
S0022-3263(96)01098-5 CCC: $12.00 © 1996 American Chemical Society

Synthesis of New N-Pivot Lariat Crown Ethers
J . Org. Chem., Vol. 61, No. 21, 1996 7579
Sch em e 1
Resu lts a n d Discu ssion
Surprisingly enough, this type of lariat crown ethers
is not well-known from the literature: in the most
complete recent reference12 only a few such lariats are
listed, mostly containing a hydroxy group at the central
carbon atom of propylene bridge derived from epoxy-
containing azacrowns.13-15
Methods for the preparation of N-pivot lariat aza-
crowns can be divided into three main categories: (i)
attachment of the side arm by chemical modification of
an amino group of an aza-crown ether (N-alkylation,
N-acylation, or Michael addition of olefins); (ii) cyclization
of an N-substituted diethanolamine or N-substituted
primary amine with R,ω-oligo(ethylene glycol) ditosylate,
dimesylate, or dihalide, and (iii) Electrophilic substitution
reactions of N-CH2-A-containing azacrowns (where A
stands for an activating group that leaves after the
formation of a new bond). Method i seems to be more
effective and simpler than the other two: from it, the
yields of the lariat crowns are usually high and the
reaction is not complicated by the formation of polymers
or products of alternative cyclizations. However, method
i is not universal because of the restricted availability of
reagents used for modification. Method ii also requires
the modification of diethanolamine at an early stage by
the same procedures used for method i, i.e., alkylation,
acylation, or Michael addition need to be used to prepare
the N-substituted diethanolamine, which then is reacted
with an oligo(ethylene glycol) derivative to form a mac-
rocycle; alternatively, a primary amine could be cyclized
with an oligo(ethylene glycol) derivative to give a cyclic
product by double alkylation of the amino group. As
mentioned above, the choice of reagents for the alkylation
of diethanolamine is limited, and such reactions usually
require high-dilution techniques to avoid the formation
of polycondensation products. Furthermore, the alkyla-
tion of diethanolamine required the use of inorganic
bases, e.g., sodium carbonate, and it was difficult to
remove residual salts, therefore making purification of
N-alkylated diethanolamines difficult.3 Cyclizations in-
volving primary amines (method of Calverley and Dale16)
are generally suitable only for small-sized macrocycles.3
Method iii is mostly represented by the reactions of
N-(methoxymethyl) derivatives of azacrowns with various
CH or NH active compounds and can be considered a
variation of the Mannich reaction; this method was
developed by Luk’yanenko et al.17,18
i or ii, 3-(halogen-substituted)propyl alkyl ethers, are not
readily available. 3-Aminopropanol was utilized3 as a
starting material in the synthesis of N-(3-hydroxypropyl)-
aza-12-crown-4 according to the method of Calverley and
Dale but was not used for the syntheses of larger
macrocycles (15- or 18-membered rings). Finally, al-
though Mannich reactions of N-(methoxymethyl) deriva-
tives of azacrowns with phenols10,11 lead to the formation
of the above-mentioned three-carbon atom chain, this
now includes two sp2 aromatic ring carbon atoms, which
diminishes the side-arm mobility.
We recently found that an addition of N-(benzotria-
zolylmethyl)-substituted secondary amines to electron-
rich olefins (vinyl ethers19 or vinyl amides20 ), catalyzed
by Lewis acids, gives the corresponding Markovnikov-
type products of addition of Bt- and R2N+dCH2 in almost
quantitative yields. Furthermore, these products were
successfully reduced in order to remove the benzotriazole
moiety, forming 3-(amino-substituted)propyl alkyl ethers
or variously substituted 1,3-diaminopropanes (Scheme 1)
in quite high yields (65-94%).19,20 We have now em-
ployed this synthetic pathway in the preparation of
N-pivot lariat crowns containing propylene-bridging units
in the side arm.
Examination of the above methods demonstrates that
they are not convenient for the preparation of N-pivot
lariats with three carbon atoms between the ring and the
side arm donor. Firstly, the analogs of 2-(halogen-
substituted)ethyl alkyl ethers previously used for the
preparation of N-pivot lariat azacrowns3 by the methods
We anticipated that reactions of the Mannich-type
adduct 1, prepared directly from diethanolamine (1a , R
) R1 ) CH2CH2OH), with ethers 2 or amides 5, followed
by reduction of the intermediate addition products,
should access the desired building blocks with propylene
linkages (4, 7). We isolated the adduct 1a as a solid in
fair yield when 1-(hydroxymethyl)benzotriazole was re-
acted with diethanolamine in refluxing benzene for an
(12) Bradshaw, J . S.; Krakowiak, K. E.; Izatt, R. M. Aza-crown
Macrocycles; The Chemistry of Heterocyclic Compounds Series; J ohn
Wiley & Sons: Inc.: New York, 1993; Vol. 51, 885 pp.
(13) Belohradsky, M.; Stibor, I.; Holy, P.; Zavada, J . Collect. Czech.
Chem. Commun. 1987, 52, 2500.
(14) Belohradsky, M.; Holy, P.; Stibor, I.; Zavada, J . Collect. Czech.
Chem. Commun. 1987, 52, 2961.
(15) Zavada, J .; Koudelka, J .; Holy, P.; Belohradsky, M.; Stibor, I.
Collect. Czech. Chem. Commun. 1989, 54, 1043.
(16) Calverley, M. J .; Dale, J . J . Chem. Soc., Chem. Commun. 1981,
684.
(17) Bogatsky, A. V.; Lukyanenko, N. G.; Pastushok, V. N.; Kosty-
anovsky, R. G. Synthesis 1983, 992.
(18) Lukyanenko, N. G.; Pastushok, V. N.; Bordunov, A. V.; Ivanov,
E. I.; Kalayanov, G. D.; Yaroshchenko, I. Ya. Chem. Heterocycl. Compd.
(Engl. Transl.) 1993, 239.
(19) Katritzky, A. R.; Rachwal, S.; Rachwal, B.; Steel, P. J . J . Org.
Chem. 1992, 57, 4932.
(20) Katritzky, A. R.; Rachwal, S.; Rachwal, B. J . Org. Chem. 1994,
59, 5206.

7580 J . Org. Chem., Vol. 61, No. 21, 1996
Katritzky et al.
Sch em e 2
Sch em e 3
extended reaction time. However, reaction of 1a with
vinyl ethers 2 (2a , R2 ) Et; 2b, R2 ) i-Bu) failed because
a competing side reaction prevailedsformation of 2-ben-
zotriazolyl-3-oxa-5-methylhexane (9d ) and 2-benzotria-
zolyl-3-oxapentane (9e), respectively (Scheme 2). This
type of side product is generally formed in such reactions,
as the NMR spectra of crude reaction products showed.
Presumably, the presence of hydroxy groups in the
structure of 1a that easily release protons makes the side
reaction dominant; i.e., the more acidic the protons in
the reaction components are, the more the side product
is formed. We avoided the formation of such undesirable
side products by preparing bis(O-silylated) diethanola-
mine 8b in 91% yield from diethanolamine and hexa-
methyldisilazane, according to the general silylation
method.21 Subsequently, 8b was condensed with 1-(hy-
droxymethyl)benzotriazole in benzene yielding the adduct
1b, which after removal of solvent and without further
purification reacted with vinyl ethers 2a -c to afford
R-benzotriazolyl-substituted O-silylated ethers 9a -c. The
crude addition products 9a -c were conveniently hydro-
lyzed by methanol-water to the diols 10a -c (Scheme 2).
Taking into account Scheme 1, two possible pathways
to prepare N-pivot azacrowns were considered: first,
reduction of diols 10a -c (removal of benzotriazole moi-
ety) followed by cyclization with oligo(ethylene glycol)
ditosylates, and second, cyclization of derivatives 10a -c
followed by reduction of the preformed macrocycles.
Reduction of the ether 10b with LiAlH4 was performed
in refluxing THF for 2 days. However, we were unable
to separate the amino ether thus formed from inorganics
by extraction even after careful adjustment of pH of the
reaction mixture. Therefore, we utilized the second
pathway, i.e., cyclization of the ethers 10a -c with
ditosylates 11a ,b by refluxing in THF containing a small
excess of sodium hydride for 2 days (Scheme 3). We used
ethers 10a -c directly after isolation, without additional
purification; their structures were confirmed by NMR
spectra and by following transformations into macro-
cycles 12a-e. Benzotriazole-containing macrocycles 12a-
e, which have alkyl propyl ethers as side arms, were
isolated after column chromatography in yields of 50%
and higher. The reaction rate is very slow: attempted
isolation of the macrocycles 12a -e after 1 day of reflux
led to the yields of target compounds of 28% (12b) to 40%
(12c). Lariat ether 12e was isolated only in 28% yield,
presumably because of polymerization of allyl diol 10c
during cyclization upon action of high temperature. The
conditions both in this reaction and in the following
reduction could be optimized, and the yields improved.
Our new preparation of these and the following lariat
azacrowns is briefly summarized in Table 1.
Lariats 13a -d were obtained after reduction of their
precursors 12a -d with LiAlH4 in refluxing THF after 2
days. In contrast to reduction of 10b (see above), the
final crowns were easy to isolate after simple workup;
they were purified by column chromatography followed
by Kugelrohr distillation (100-150 °C/0.09 Torr).
Considering the growing interest in the biological
activity of aza-crown ethers,12 and also the fact that many
1,3-disubstituted diaminopropane derivatives possess
well-known therapeutic properties,22 we elaborated a new
synthesis of N-pivot lariats containing a tertiary amino
group at the end of the propylene side arm (Scheme 4).
Addition of the protected diol 1b to enamides 5a ,b led to
the formation of benzotriazolyl-substituted amides 14a ,b;
again, these were easily hydrolyzed to give deprotected
products 15a ,b in excellent yields (90% and 98%, respec-
tively). However, their attempted cyclization with di-
tosylates 11a ,b to afford macrocyclic lariat-amides 16a ,b
failed: no appreciable amount of macrocycles 16a ,b was
detected after 2 days of reflux of equimolar amounts of
15a ,b with either 11a or 11b in THF in the presence of
NaH. Therefore, we considered another route for prepa-
ration of the macrocycles 16a ,b (Scheme 4). Modification
of the method of Calverley and Dale,16 which consisted
of the replacement of acetonitrile used as a solvent in
the previous method by much less polar toluene, gave
the protected macrocycle 18a in 86% yield. This modi-
fication may be useful in the preparation of the other
lariat azacrowns, since it employs more accessible tosy-
lates instead of iodides and toluene instead of acetonitrile.
Subsequent removal of the protecting group by hydro-
(22) Windholz, M., Budavari, S., Blumetti, R. F., Otterbein, E. S.,
Eds. The Merck Index-An Encyclopedia of Chemicals, Drugs and
Biologicals; Merck & Co., Inc.: Rahway, NJ , 1983; 1071 pp.
(21) Mormann, W.; Leukel, G. Synthesis 1988, 990.

Synthesis of New N-Pivot Lariat Crown Ethers
J . Org. Chem., Vol. 61, No. 21, 1996 7581
Ta ble 1. New P r ep a r a tion s of Br a cch ia l La r ia t Eth er s: Der iva tives of 1-Aza -15-cr ow n -5 (A) a n d 1-Aza -18-cr ow n -6 (B)
crown/yielda
(%)
crown/yielda
(%)
side-arm structure
side-arm structure
-(CH2)2CH(Bt)OCH2CH3b (12a )
A/54
B/50
A/56
B/62
A/28
A/40
B/38
A/45
-(CH2)3OCH2CH(CH3)2 (13d )
-CH2Btb (19)
A/45
A/97
A/75
A/81
A/52
A/59
b
-(CH2)2CH(Bt)OCH2CH3 (12b)
-(CH2)2CH(Bt)OCH2CH(CH3)2b (12c)
-(CH2)2CH(Bt)OCH2CH(CH3)2b (12d )
-(CH2)2CH(Bt)OCH2CHdCH2b (12e)
-(CH2)3OCH2CH3 (13a )
-(CH2)3OCH2CH3 (13b)
-(CH2)3OCH2CH(CH3)2 (13c)
-(CH2)2CH(Bt)N(CH3)COCH3b (16a )
-[3-Bt-3-(2-oxopyrrolidin-1-yl)propyl]b (16b)
-(CH2)3N(CH3)CH2CH3 (17a )
-[3-(pyrrolidin-1-yl)propyl] (17b)
a
b
Yields of isolated products. Bt ) N-benzotriazolyl.
Ta ble 2. Ca tion Com p lexa tion Con sta n ts for Br a cch ia l
La r ia t Eth er s
Sch em e 4
a
log KS
compd structure
18-crown-6
Na+
K+
ref
4.32 6.03 this work
4.35 6.08 24
3.50 4.92 25
18-crown-6
b
18N CH2CH2CH3
18N CH2CHdCH2
3.58 5.02 25
18N CH2CH2OCH3
4.58 5.67 26
18N CH2CH2CH2OCH2CH3 (13b)
3.67 4.56 this work
18N CH2CH2CH(Bt)OCH2CH3 (12b) 3.84 4.53 this work
18N CH2CH2CH(Bt)OCH2CH(CH3)2 3.59 4.57 this work
(12d )
18N CH2CONHCH(s-Bu)COOCH3
4.03 5.10 27
a
b
Measured in anhyd methanol at 25.0 ( 0.1 °C. 18N
represents 1-aza-18-crown-6.
containing ethers 12a ,b,d ,e and afforded the correspond-
ing N,N′-bridged unsymmetrical diamines 17a ,b in good
yields.
Com p lexa tion Stu d y. Homogeneous sodium, potas-
sium, calcium, and ammonium cation-binding constants
(log KS) have been reported for nearly 100 N-pivot lariat
ethers having ring sizes that vary from 12- to 18-
members. Cation-binding data (in anhyd methanol at
25.0 ( 0.1 °C) for several of the novel lariats reported
herein are recorded in Table 2. Crown ethers are
designated using an abbreviated form of the macroring.23
The symbol 00 represents a crown ether having 00
members. Thus, 18-crown-6 can be abbreviated as 18 .
Azalariats having 18-membered rings and having side
arms attached at nitrogen can be represented as R N18 .
In all cases recorded in Table 2, the lariat ether side arms
are attached to nitrogen.
Sodium and potassium cation binding by macrocycles
is favored by oxygen over nitrogen donors. Thus, re-
placement of O in 18-crown-6 by NCH2CH2CH3 leads to
a loss of binding strength of approximately 10-fold for
both cations. This is true whether the side chain is
saturated (n-propyl) or unsaturated (allyl). When the
terminal methyl group of propyl is replaced by a methoxy
group, the additional donor group boosts the Na+ binding
strength by 10-fold (3.58-4.58). The increase in K+-
binding was smaller (4.92-5.67) but still substantial.
When the oxygen donor atom is moved away from the
ring by a single carbon, both Na+ and K+ binding
genation, according to the procedure described earlier,3
afforded aza-15-crown-5 18b in 89% yield (after column
chromatography). 1-(Benzotriazolylmethyl)aza-15-crown-5
(19) was readily prepared in excellent yield from 1-(hy-
droxymethyl)benzotriazole and aza-15-crown-5 in EtOH;
it was further reacted with enamides 5a ,b in the presence
of BF3‚Et2O in refluxing dry benzene. The corresponding
macrocyclic amides 16a ,b were isolated and purified by
column chromatography to give 75% and 81% of pure
products, respectively. Their structures were confirmed
by NMR and C,H,N analysis data. Reduction of the
amides 16a ,b was completed in much shorter reaction
time compared to the reduction of the benzotriazole-
(23) Hernandez, J . C.; Trafton, J . E.; Gokel, G. W. Tetrahedron Lett.
1991, 32, 6269.
(24) Gokel, G. W.; Goli, D. M.; Minganti, C.; Echegoyen, L. J . Am.
Chem. Soc. 1983, 105, 6786.
(25) Arnold, K. A.; Hernandez, J . C.; Li, C.; Mallen, J . V.; Nakano,
A.; Schall, O. F.; Trafton, J . E.; Tsesarskaja, M.; White, B. D.; Gokel,
G. W. Supramol. Chem. 1995, 5, 45.
(26) Schultz, R. A.; Dishong, D. M.; Gokel, G. W. J . Am. Chem. Soc.
1982, 104, 625.
(27) White, B. D.; Arnold, K. A.; Gokel, G. W. Tetrahedron Lett. 1987,
28, 1749.

7582 J . Org. Chem., Vol. 61, No. 21, 1996
Katritzky et al.
assignments. 1-(Hydroxymethyl)benzotriazole was prepared
as previously described.33
decrease by essentially 10-fold. This is almost certainly
a conformational effect since the gauche conformation of
XCCX is lower in energy than the gauche conformation
of XCCCX. Indeed, it is likely that the X-C and C-C-X
bonds will prefer to be trans (anti). In the anti conforma-
tion, the heteroatoms do not organize into the required
chelate. There may also be some steric hindrance as-
sociated with the ethoxy group compared to methoxy
substituent in 18N CH2CH2OMe, although in the series
18N CH2COOR, in which R ) ethyl, n-decyl, or n-
octadecyl, log KS values for either Na+ or K+ vary by less
than 0.1 log unit.
Bis[2-(tr im eth ylsiloxy)eth yl]a m in e (8b). The protected
diethanolamine was prepared according to the general litera-
ture procedure21 and was used without further purification.
1
Colorless low-density liquid, yield 91%; H NMR δ 3.65 (t, J
) 5.4 Hz, 4H), 2.69 (t, J ) 5.4 Hz, 4H), 0.07 (s, 18H); 13C NMR
δ 61.8, 51.5, -0.6. Anal. Calcd for C10H27NO2Si2: C, 48.13;
H, 10.91; N, 5.62. Found: C, 47.83; H, 11.15; N, 5.53.
(Ben zot r ia zolylm et h yl)b is[2-(t r im et h ylsiloxy)et h yl]-
a m in e (1b). A mixture of bis-[2-(trimethylsiloxy)ethyl]amine
(8b) (2.5 g, 10.0 mmol) and 1-(hydroxymethyl)benzotriazole
(1.59 g, 10.7 mmol) in benzene (50 mL) was refluxed for 24 h.
The solvent was evaporated in vacuo to give 3.7 g (97%) of a
colorless viscous oil: 1H NMR δ 8.15 (d, J ) 8.0 Hz, 1H), 7.98
(dd, J ) 2.7, 6.2 Hz, 2H), 7.88 (d, J ) 8.0 Hz, 1H), 7.59-7.42
(m, 2H + 1H), 5.74 (s, 2H), 3.80 (t, J ) 5.6 Hz, 4H), 3.78 (t, J
) 5.6 Hz, 4H), 3.07 (t, J ) 5.6 Hz, 4H), 3.00 (t, J ) 5.6 Hz,
4H), 0.21 (s, 18H); 13C NMR δ 145.9, 144.2, 133.6, 127.1, 123.6,
119.6, 118.2, 110.5, 75.3, 68.2, 61.4, 61.0, 54.8, 54.6, -0.6. Anal.
Calcd for C17H32N4O2Si2: C, 53.64; H, 8.47. Found: C, 53.43;
H, 8.45.
Steric hindrance almost certainly is a problem for the
two novel lariats 18N CH2CH2CH(Bt)OEt (12b) and
18N CH2CH2CH(Bt)OCH2CH(CH3)2 (12e), but only for
the smaller Na+ cation. Potassium binding strengths for
these to compounds are essentially identical, suggesting
that when the larger cation is ring-bound, the side arm
and the associated ethyl or isobutyl group is too remote
to affect the binding conformation. The steric crowding
appears to exact a 2-fold price in the Na+-binding case.
These new compounds are also compared to the previ-
ously reported 18N CH2CONHCH(s-Bu)COOCH3, which
possesses a sec-butyl group. This isoleucine (gly-ile)
derivative probably uses the proximal carbonyl donor for
binding, as found in the solid state structures of the two-
armed gly-gly esters.28
Gen er a l P r oced u r e for th e P r ep a r a tion of N-[3-Ben -
z o t r i a z o ly l-4-o x a -4-(s u b s t i t u t e d )]-N ,N -d i e t h a n o l-
a m in es 10a -c. A mixture of amine 1b (6 mmol), the
corresponding vinyl ether 2a -c (9 mmol), boron trifluoride
etherate (2 drops), and dry benzene (50 mL) was stirred and
heated at 80 °C for 24 h (a sealed tube was used in the case of
2a ). After cooling, benzene and unreacted vinyl ether 2 were
removed under reduced pressure, the residue was dissolved
in methanol (50 mL), and water was added until the solution
became milky (approximately 3-5 mL). The obtained mixture
was refluxed for 1.5 h, and then methanol was evaporated in
vacuo. Water (50 mL) was added to the residue, which was
extracted with ether (100 mL) and then with CH2Cl2 (100 mL).
The combined organic extracts were washed with water and
dried over anhyd MgSO4. After solvent removal the diol 10
was obtained as a yellow viscous oil, which was used without
further purification in the next step. The analytical samples
of 10a -c were obtained using column chromatography (eluent
CHCl3:methanol 20:1).
N -(3-B e n z o t r i a z o ly l-4-o x a h e x y l)-N ,N -d i e t h a n o l-
a m in e (10a ): yellow oil; yield quantitative; 1H NMR δ 8.08
(d, J ) 8.3 Hz, 1H), 7.91 (dd, J ) 3.1, 6.7 Hz, 2H), 7.80 (d, J
) 8.3 Hz, 1H), 7.52-7.38 (m, 2H + 2H), 6.33 (t, J ) 6.3 Hz,
1H), 6.17 (t, J ) 6.3 Hz, 1H), 3.62-3.44 (m, 7H), 3.38-3.22
(m, 1H), 2.78-2.66 (m, 2H), 2.62-2.37 (m, 6H), 1.17 (t, J )
7.0 Hz, 3H), 1.13 (t, J ) 7.0 Hz, 3H); 13C NMR δ 144.0, 127.6,
126.9, 124.3, 120.1, 118.5, 118.4, 111.1, 93.2, 88.7, 65.3, 64.6,
59.5, 59.4, 56.1, 55.9, 49.2, 32.9, 14.6.
An important difference between 18N CH2CONHCH-
(s-Bu)COOCH3 and 12e is that the donor group in the
former case is known to be an amide carbonyl, whereas
in the present case either the ether oxygen or one of the
benzotriazole nitrogen atoms may interact with the ring-
bound cation. On the basis of donicities, it is presumed
that O rather than N served as ligand, but this is not
known with certainty. A weaker donor in a more
favorable position may lead to a more stable complex
than a stronger donor inappropriately positioned for
interaction.
In conclusion, we have elaborated a new synthetic
approach to the preparation of N-pivot lariat aza-crown
ethers containing 3-oxo- and 3-azapropylene units in the
side arm, which involves the addition reactions of Man-
nich-type benzotriazole derivatives of diethanolamine or
of aza-crown ethers to vinyl ethers or vinylamides, with
subsequent reduction of the benzotriazolyl substituent
in the addition products.
N-(3-Ben zotr ia zolyl-4-oxa -6-m eth ylh ep tyl)-N,N-d ieth -
a n ola m in e (10b): dense yellow oil; yield quantitative; 1H
NMR δ 8.09 (d, J ) 8.3 Hz, 1H), 7.92 (dd, J ) 3.14, 6.7 Hz,
2H), 7.79 (d, J ) 8.3 Hz, 1H), 7.52-7.38 (m, 2H + 2H), 6.28
(t, J ) 6.4 Hz, 1H), 6.13 (dd, J ) 5.3, 6.7 Hz, 1H), 3.60-3.43
(m, 6H), 3.32-3.25 (m, 1H), 3.03 (dd, J ) 6.6, 9.1 Hz, 1H),
2.92 (dd, J ) 6.9, 8.9 Hz, 1H), 2.80-2.60 (m, 2H), 2.60-2.38
(m, 4H + 2H), 1.90-1.75 (m, 1H), 0.92-0.77 (m, 6H); 13C NMR
δ 144.0, 127.6, 126.9, 125.6, 124.4, 120.1, 118.4, 115.0, 111.2,
93.7, 89.1, 76.5, 75.8, 59.6, 59.5, 56.1, 56.0, 50.1, 50.0, 49.4,
32.9, 32.5, 28.2, 28.1, 19.4, 19.2, 19.1, 19.0.
Exp er im en ta l Section
Gen er a l. See refs 29 and 30. 1H NMR spectra were
recorded at 300 MHz and 13C NMR spectra at 75 MHz in
CDCl3. Cation-binding constants were measured according to
the method of Frensdorff31 as described recently in detail.32
All the compounds containing a benzotriazole moiety that are
described in the present paper consist of the mixture of
benzotriazol-1-yl (Bt1) and benzotriazol-2-yl (Bt2) isomers in
different ratios; both isomers readily undergo the transforma-
tions described here, and therefore, their isolation was not
performed. The Experimental Section contains NMR data of
the mixtures of Bt1 and Bt2 isomers, without their complete
N-(3-Ben zotr ia zolyl-4-oxa h ep t-6-en yl)-N,N-d ieth a n ola -
1
m in e (10c): dense yellow oil; yield quantitative; H NMR δ
8.07 (d, J ) 8.3 Hz, 1H), 7.90 (dd, J ) 3.1, 6.7 Hz, 2H), 7.79
(d, J ) 8.3 Hz, 1H), 7.49 (t, J ) 7.1 Hz, 1H), 7.47-7.37 (m, 1H
+ 2H), 6.37 (t, J ) 6.4 Hz, 1H), 6.21 (t, J ) 6.3 Hz, 1H), 5.86-
5.72 (m, 1H), 5.32-5.13 (m, 2H), 4.01-3.78 (m, 2H), 3.70-
3.45 (m, 6H), 2.78-2.48 (m, 6H), 2.36-2.24 (m, 1H); 13C NMR
δ 146.6, 144.0, 134.6, 132.6, 131.4, 127.7, 126.9, 124.4, 120.0,
118.5, 118.4, 111.1, 92.3, 87.8, 70.3, 69.7, 67.9, 61.4, 59.6, 59.5,
59.4, 58.8, 58.0, 57.4, 56.2, 56.0, 50.0, 35.0, 32.8, 32.4.
(28) White, B. D.; Fronczek, F. R.; Gandour, R. D.; Gokel, G. W.
Tetrahedron Lett. 1987, 28, 1753.
(29) Katritzky, A. R.; Rachwal, B.; Rachwal, S.; Abboud, K. A. J .
Org. Chem. 1996, 61, 3117.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-[3-(Ben -
zotr iazolyl)-4-oxa-4-(su bstitu ted)]aza-Cr own Eth er s 12a -
(30) Katritzky, A. R.; Xie, L. J . Org. Chem. 1995, 60, 3707.
(31) Frensdorff, H. K. J . Am. Chem. Soc. 1971, 93, 600.
(32) Arnold, K. A.; Gokel, G. W. J . Org. Chem. 1986, 51, 5015.
(33) Burckhalter, J . H.; Stephens, V. C.; Hall, L. A. R. J . Am. Chem.
Soc. 1952, 74, 3868.

Synthesis of New N-Pivot Lariat Crown Ethers
J . Org. Chem., Vol. 61, No. 21, 1996 7583
e. A mixture of substituted diethanolamine 10a -c (12 mmol)
and the corresponding oligo(ethylene glycol)ditosylate 11a ,b
(12 mmol) in dry THF (100 mL) was added dropwise to the
refluxing and stirring suspension of NaH (0.8 g, 33 mmol) in
dry THF (200 mL) under nitrogen. The reaction mixture was
stirred and refluxed under nitrogen for 2 days, cooled, and
quenched with water. The organic layer was separated, and
the water fraction was extracted with ether (50 mL) and CH2-
Cl2 (50 mL). The combined organic layers were dried over
anhyd MgSO4. The solvents were evaporated in vacuo, and
the oily residue was purified by column chromatography
(eluent ethyl acetate:hexanes 1:3, followed by gradual replace-
ment of hexanes with ethyl acetate).
cooled, and the excess LiAlH4 was carefully quenched with
water. The suspension obtained was treated with 5 mL of a 1
N aqueous solution of NaOH and then with 5 mL of water.
The white sticky precipitate was filtered off and washed with
water (10 mL) and THF (10 mL). The filtrate was extracted
with ether (2 × 30 mL) and CH2Cl2 (30 mL), and the organic
layers were separated and dried over anhyd. MgSO4. The
solvents were removed in vacuo, and the residual oily reaction
products were purified by column chromatography (eluent
ethyl acetate:hexanes 1:3, followed by gradual replacement of
hexanes with ethyl acetate) and then by distillation (Kugelrohr
apparatus, 100-150 °C/0.09 Torr) to give lariats 13a ,b as
viscous pale-yellow liquids.
13-(3-Ben zotr ia zolyl-4-oxa h exyl)-1,4,7,10-tetr a oxa -13-
a za cyclop en ta d eca n e (12a ): heavy yellow oil; yield 54%; 1H
NMR δ 8.07 (d, J ) 8.3 Hz, 1H), 7.80 (d, J ) 8.3 Hz, 1H), 7.48
(t, J ) 7.1 Hz, 1H), 7.38 (t, J ) 7.1 Hz, 1H), 6.26 (dd, J ) 1.1,
6.0 Hz, 1H), 3.70-3.46 (m, 17H), 3.27 (dq, J ) 7.0, 9.4 Hz,
1H), 2.71 (t, J ) 6.0 Hz, 4H), 2.62-2.55 (m, 2H), 2.50-2.38
(m, 1H), 2.28-2.16 (m, 1H), 1.13 (t, J ) 7.0 Hz, 3H); 13C NMR
δ 146.6, 131.6, 127.3, 124.0, 119.9, 111.2, 88.4, 71.0, 70.5, 70.1,
70.0, 64.5, 54.8, 51.8, 33.1, 14.7. Anal. Calcd for C21H34N4O5:
N, 13.26. Found: N, 13.68.
16-(3-Ben zotr ia zolyl-4-oxa h exyl)-1,4,7,10,13-p en ta oxa -
16-a za cycloocta d eca n e (12b): dense yellow oil; yield 50%;
1H NMR δ 8.07 (d, J ) 8.3 Hz, 1H), 7.90 (dd, J ) 3.1, 6.7 Hz,
2H), 7.80 (d, J ) 8.3 Hz, 1H), 7.48 (t, J ) 7.1 Hz, 1H), 7.43-
7.35 (m, 2H + 1H), 6.25 (d, J ) 6.4 Hz, 1H), 6.08 (t, J ) 6.4
Hz, 1H), 3.70-3.50 (m, 20H), 3.40-3.24 (m, 2H), 2.80-2.70
(m, 4H), 2.64-2.56 (m, 2H), 2.52-2.20 (m, 2H), 1.15 (dt, J )
7.0, 8.8 Hz, 3H); 13C NMR δ 146.5, 144.0, 131.5, 127.2, 126.5,
124.0, 119.9, 118.5, 111.2, 93.3, 88.5, 70.7, 70.6, 70.2, 69.7, 69.6,
65.1, 64.4, 54.1, 50.8, 33.1, 32.7, 14.7, 14.6. Anal. Calcd for
C23H38N4O6: N, 12.01. Found: N, 12.31.
13-(4-Oxa h exyl)-1,4,7,10-tetr a oxa -13-a za cyclop en ta d e-
ca n e (13a ): viscous yellow oil; yield 40%; 1H NMR δ 3.70-
3.62 (m, 16H), 3.45 (q, J ) 7.0 Hz, 2H), 3.44 (t, J ) 6.5 Hz,
2H), 2.76 (t, J ) 6.1 Hz, 4H), 2.59 (t, J ) 7.4 Hz, 2H), 1.73
(quintet, J ) 7.5 Hz, 2H), 1.19 (t, J ) 7.0 Hz, 3H); 13C NMR
δ 70.9, 70.4, 70.1, 70.0, 68.7, 66.0, 54.6, 53.6, 27.7, 15.2; HRMS
calcd for C15H31NO5 305.2202 (M+), found 305.2196.
16-(4-Oxa h exyl)-1,4,7,10,13-p en ta oxa -16-a za cycloocta -
d eca n e (13b): viscous yellow oil; yield 38%; 1H NMR δ 3.70-
3.59 (m, 20H), 3.45 (q, J ) 7.0 Hz, 2H), 3.44 (t, J ) 6.5 Hz,
2H), 2.76 (t, J ) 6.0 Hz, 4H), 2.59 (t, J ) 7.4 Hz, 2H), 1.72
(quintet, J ) 7.5 Hz, 2H), 1.19 (t, J ) 7.0 Hz, 3H); 13C NMR
δ 70.8, 70.7 (2C), 70.3, 69.9, 68.6, 65.9, 54.0, 52.6, 27.5, 15.1;
HRMS calcd for C17H36NO6 350.2542 (M+ + 1), found 350.2540.
13-(4-Oxa -6-m eth ylh ep tyl)-1,4,7,10-tetr a oxa -13-a za cy-
clop en ta d eca n e (13c): viscous yellow oil; yield 45%; 1H NMR
δ 3.69-3.61 (m, 16H), 3.42 (t, J ) 6.5 Hz, 2H), 3.15 (d, J )
6.7 Hz, 2H), 2.75 (t, J ) 6.0 Hz, 4H), 2.60 (t, J ) 7.3 Hz, 2H),
1.92-1.78 (m, 1H), 1.78-1.67 (m, 2H), 0.89 (d, J ) 6.7 Hz,
6H); 13C NMR δ 77.7, 70.9, 70.4, 70.0, 68.9, 54.5, 53.5, 28.3,
27.6, 19.3. Anal. Calcd for C17H35NO5: N, 4.20. Found: N,
4.60.
16-(4-Oxa -6-m eth ylh ep tyl)-1,4,7,10,13-p en ta oxa -16-a za -
cycloocta d eca n e (13d ): viscous yellow oil; yield 45%; 1H
NMR δ 3.98-3.59 (m, 20H), 3.43 (t, J ) 6.4 Hz, 2H), 3.15 (d,
J ) 6.7 Hz, 2H), 2.76 (t, J ) 6.0 Hz, 4H), 2.59 (t, J ) 7.1 Hz,
2H), 1.92-1.78 (m, 1H), 1.78-1.67 (m, 2H), 0.89 (d, J ) 6.7
Hz, 6H); 13C NMR δ 77.7, 70.8, 70.7, 70.3, 69.9, 68.9, 54.0, 52.6,
28.3, 27.4, 19.3; HRMS calcd for C19H39NO6 377.2777 (M+),
found 377.2781.
13-Ben zyl-1,4,7,10-t et r a oxa -13-a za cyclop en t a d eca n e
(18a ). A solution of penta(ethylene glycol)ditosylate (5.00 g,
9 mmol) in toluene (75 mL) and a solution of benzylamine (0.98
g, 9 mmol) in toluene (75 mL) were slowly and simultaneously
added from two dropping funnels to the vigorously stirred
suspension of anhyd sodium carbonate (4.80 g, 45 mmol) in
toluene (250 mL). The mixture was refluxed and stirred for 3
days. The suspension formed was cooled, solids were filtered
off, and methanol (35 mL) was added to the filtrate. A solution
was heated at 50 °C for 30 min, cooled, and then concentrated
in vacuo to give the light yellow oil, which was purified by
column chromatography (eluent ethyl acetate:hexanes 1:1).
Yield of N-benzyl-protected crown 18a : 86%. The 1H NMR
spectrum of the isolated crown was consistent with previously
published data.3
13-(3-Ben zot r ia zolyl-4-oxa -6-m et h ylh ep t yl)-1,4,7,10-
tetr a oxa -13-a za cyclop en ta d eca n e (12c): heavy yellow oil;
1
yield 56%; H NMR δ 8.07 (d, J ) 8.3 Hz, 1H), 7.90 (dd, J )
3.1, 6.7 Hz, 2H), 7.78 (d, J ) 8.3 Hz, 1H), 7.47 (dt, J ) 1.0, 7.0
Hz, 1H); 7.42-7.35 (m, 1H), 6.22 (dd, J ) 1.6, 5.8 Hz, 1H),
6.04 (m, 1H), 3.70-3.56 (m, 16H), 3.26 (dd, J ) 6.4, 9.0 Hz,
1H), 2.94 (dd, J ) 6.4, 9.0 Hz, 1H), 2.72 (t, J ) 6.0 Hz, 4H),
2.60 (t, J ) 6.7 Hz, 2H), 2.50-2.40 (m, 1H), 2.30-2.15 (m, 1H),
1.87-1.73 (m, 1H), 0.83 (d, J ) 6.7 Hz, 3H), 0.79 (d, J ) 6.7
Hz, 3H); 13C NMR δ 146.7, 131.5, 127.2, 124.0, 119.9, 111.3,
88.9, 75.6, 71.0, 70.5, 70.1, 70.0, 54.8, 51.9, 33.1, 28.2, 19.2.
Anal. Calcd for C23H38N4O5: N, 12.44. Found: 12.45.
16-(3-Ben zotr ia zolyl-4-oxa -6-m eth ylh ep tyl)-1,4,7,10,13-
p en ta oxa -16-a za cycloocta d eca n e (12d ): dense yellow oil;
1
yield 62%; H NMR δ 8.07 (d, J ) 8.3 Hz, 1H), 7.90 (dd, J )
3.1, 6.7 Hz, 2H), 7.78 (d, J ) 8.3 Hz, 1H), 7.50-7.35 (m, 4H),
6.20 (dd, J ) 1.1, 6.0 Hz, 1H), 6.02 (t, J ) 6.4 Hz, 1H), 3.70-
3.54 (m, 20H), 3.31-3.23 (m, 2H), 3.08 (dd, J ) 2.7, 6.4 Hz,
1H), 2.93 (dd, J ) 2.2, 6.7 Hz, 1H), 2.77-2.71 (m, 4H), 2.62-
2.57 (m, 2H), 2.50-2.20 (m, 2H), 1.85-1.78 (m, 1H), 0.89-
0.77 (m, 6H); 13C NMR δ 144.1, 127.2, 126.5, 124.1, 120.0,
118.5, 111.3, 93.7, 89.0, 70.8, 70.7, 70.4, 69.9, 69.8, 54.1, 51.1,
50.8, 33.3, 28.2, 19.2, 19.1, 19.0; HRMS calcd for C25H43N4O6
495.3182 (M+ + 1), found 495.3180.
13-[3-(Ben zot r ia zol-2-yl)-4-oxa -h ep t -6-en yl]-1,4,7,10-
tetr a oxa -13-a za cyclop en ta d eca n e (12e): yellow oil; yield
1,4,7,10-Tetr a oxa -13-a za cyclop en ta d eca n e (18b). Hy-
drogenation and purification of 13-benzyl-1,4,7,10-tetraoxa-
13-azacyclopentadecane (18a ) was carried out in accordance
with the method described in literature.3 Yield of aza-crown
1
28%; H NMR δ 7.90 (dd, J ) 3.1, 6.7 Hz, 2H), 7.40 (dd, J )
3.1, 6.7 Hz, 2H), 6.13 (t, J ) 6.4 Hz, 1H), 5.89-5.75 (m, 1H),
5.25 (ddd, J ) 1.5, 2.8, 17.2 Hz, 1H, cis-CH2dCH-), 5.15 (ddd,
J ) 1.5, 2.8, 10.3 Hz, 1H, trans-CH2dCH-), 4.03-3.89 (m,
2H), 3.69-3.56 (m, 16H), 2.73 (t, J ) 5.8 Hz, 4H), 2.65-2.35
(m, 4H); 13C NMR δ 144.1, 132.9, 126.6, 118.5, 118.1, 92.5,
71.0, 70.5, 70.3, 70.1, 70.0, 54.7, 51.5, 33.4. Anal. Calcd for
C22H34N4O5: C, 60.81; H, 7.89; N, 12.89. Found: C, 60.46; H,
8.14; N, 13.31.
1
18b: 89%. The H NMR spectrum of the isolated crown was
consistent with previously published data.3
13-(Ben zotr ia zolylm eth yl)-1,4,7,10-tetr a oxa -13-a za cy-
clop en ta d eca n e (19). A solution of the aza-crown 18b (0.50
g, 2.3 mmol) and 1-(hydroxymethyl)benzotriazole (0.34 g, 2.3
mmol) in ethanol (25mL) was stirred under reflux for 1 h. The
solvent was evaporated in vacuo, and the resulting colorless
oil was dried on a vacuum line for 48 h: viscous oil; yield 97%;
1H NMR δ 8.03 (d, J ) 7.8 Hz, 1H), 7.84 (dd, J ) 2.6 and 6.5
Hz, 2H), 7.70 (d, J ) 7.8 Hz, 1H), 7.44 (t, J ) 7.8 Hz, 1H),
7.42-7.32 (m, 2H + 1H), 5.66 (s, 1H), 5.61 (s, 1H), 3.72-3.62
Gen er a l P r oced u r e for t h e R ed u ct ion of Ben zot r i-
a zole-Con ta in in g La r ia t Aza -Cr ow n s 12. A solution of
LiAlH4 in THF (5 mmol, 5 mL of a 1 M solution) was added in
one portion to the solution of the corresponding benzotriazole-
containing lariat aza-crown 12 (2.5 mmol) in dry THF (100
mL) under nitrogen at room temperature, and the resulting
solution was refluxed for 2 days. The reaction mixture was
(m, 16H), 3.04 (t, J ) 5.1 Hz, 4H), 2.98 (t, J ) 5.1 Hz, 4H); 13
NMR δ 145.7, 144.1, 133.5, 127.2, 126.0, 123.6, 119.6, 118.1,
C

7584 J . Org. Chem., Vol. 61, No. 21, 1996
Katritzky et al.
110.1, 75.7, 70.8, 70.2, 70.1, 69.6, 69.5, 68.2, 52.7, 52.4; HRMS
calcd for C17H37N4O4 351.2032 (M+ + 1), found 351.2033.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zotr ia -
zole-Con ta in in g La r ia t Aza -Cr ow n s 16. To a stirred
solution of 13-(benzotriazolylmethyl)-1,4,7,10-tetraoxa-13-aza-
cyclopentadecane (19) (0.62 g, 1.77 mmol) and the correspond-
ing vinylamide 5a or 5b (3 mmol) in dry benzene (50 mL) was
added BF3-etherate (1 drop) at rt, and the reaction mixture
was refluxed for 4 h. After cooling, the solvent was removed
in vacuo, and the residue was triturated with MeOH (10 mL)
for 30 min. Methanol was evaporated under reduced pressure,
and the resulting yellow oil was dissolved in CH2Cl2, washed
with water, and dried over anhyd MgSO4. The solvent was
evaporated, and the crude product was purified by column
chromatography (eluent ethyl acetate:hexanes 1:1, then CHCl3:
MeOH 20:1) to give amide 16 as a yellow oil.
13-(3-Ben zotr ia zolyl-4-a za -4-m eth yl-5-oxoh exyl)-1,4,7,-
10-tetr a oxa -13-a za cyclop en ta d eca n e (16a ): yield 75%; 1H
NMR δ 8.04 (d, J ) 8.3 Hz, 1H), 7.85 (t, J ) 3.0 Hz, 2H), 7.83
(d, J ) 8.3 Hz, 1H), 7.60-7.53 (dd, J ) 6.0, 8.6 Hz, 1H), 7.48
(t, J ) 7.2 Hz, 1H), 7.45-7.35 (m, 1H + 2H), 3.70-3.46 (m,
16H), 3.01 (s, 3H), 2.95 (s, 3H), 2.80-2.40 (m, 8H), 2.14 (s,
3H), 2.10 (s, 3H); 13C NMR 171.2, 145.5, 143.9, 133.0, 127.6,
126.6, 126.5, 124.2, 119.4, 118.3, 110.9, 71.0, 70.8, 70.6, 70.4,
70.2, 70.0, 69.9, 62.4, 55.1, 54.7, 52.2, 30.0, 28.9, 22.1, 22.0;
HRMS calcd for C22H36N5O5 450.2716 (M+ + 1), found 450.2725.
13-[3-Ben zot r ia zolyl-3-(2-oxop yr r olid in -1-yl)p r op yl]-
1,4,7,10-tetr aoxa-13-azacyclopen tadecan e (16b): yield 81%;
1H NMR δ 8.04 (d, J ) 8.3 Hz, 1H), 7.91-7.85 (m, 1H + 2H),
7.50 (t, J ) 7.1 Hz, 1H), 7.40-7.35 (m, 1H + 2H), 7.09-7.03
(m, 1H), 3.70-3.42 (m, 16H + 2H), 3.30-3.20 (m, 1H), 2.96-
2.82 (m, 1H), 2.80-2.58 (m, 5H), 2.56-2.38 (m, 3H), 2.36-
2.20 (m, 1H), 2.10-1.96 (m, 1H), 1.96-1.80 (m, 1H); 13C NMR
δ 175.1, 145.5, 132.9, 127.6, 126.5, 124.2, 119.3, 118.4, 110.7,
70.9, 70.3, 70.0, 69.95, 69.9, 61.1, 54.7, 52.0, 42.4, 30.7, 29.1,
17.7; HRMS calcd for C23H36N5O5 462.2716 (M+ + 1), found
462.2723.
Red u ction of Ben zotr ia zole-Con ta in in g La r ia t Aza -
Cr ow n s 16. Reduction of the lariats 16a ,b and isolation of
the reaction products were carried out according to the above
procedure for the lariats 12. However, amido-lariats 16 were
reduced completely after 24 h of reflux with LiAlH4 in THF to
give amino-substituted lariat azacrowns 17a ,b.
13-(4-Meth yl-4-a za h exyl)-1,4,7,10-tetr a oxa -13-a za cyclo-
1
p en ta d eca n e (17a ): yellow oil; yield 52%; H NMR δ 3.70-
3.60 (m, 16H), 2.75 (t, J ) 6.1 Hz, 4 H), 2.52 (t, J ) 7.4 Hz,
2H), 2.52 (t, J ) 7.4 Hz, 2H), 2.41 (q, J ) 7.2 Hz, 2H), 2.35 (t,
J ) 7.5 Hz, 2H), 2.21 (s, 3H), 1.70-1.62 (m, 2H), 1.05 (t, J )
7.2 Hz, 3H); 13C NMR δ 70.9, 70.6, 70.3, 70.0, 69.9, 55.1, 54.9,
54.5, 51.3, 41.5, 25.1, 12.1. Anal. Calcd for C16H34N2O4: C,
60.35; H, 10.76; N, 8.80. Found: C, 60.36; H, 10.94; N, 8.72.
13-[3-(P yr r olid in -1-yl)p r op yl]-1,4,7,10-tetr a oxa -13-a za -
1
cyclop en ta d eca n e (17b): yellow oil; yield 59%; H NMR δ
3.69-3.62 (m, 16H), 2.76 (t, J ) 6.1 Hz, 4H), 2.58-2.40 (m,
8H), 1.80-1.68 (m, 6H). 13C NMR δ 70.9, 70.4, 70.1 (2C), 55.1,
54.5 (2C), 54.2, 27.0, 23.4. Anal. Calcd for C17H34N2O4: C,
61.79; H, 10.37; N, 8.48. Found: C, 61.51; H, 10.49; N, 8.76.
J O961098W