Chelidamic acid derivatives: Precursors to functionalized pyridyl cryptands & functionalized metal ligands

Article abstract of DOI:10.1016/j.tet.2021.132333

Pyridyl cryptands, such as 12–16 formed from pyridine-2,6-dicarbonyl chloride (4) and crown ether diols 7–11, have been demonstrated to be excellent hosts for viologens (N,N′-dialkyl-4,4′-bipyridinium salts, 2) with K_a values of ～10⁴

Full text of DOI:10.1016/j.tet.2021.132333

Tetrahedron 94 (2021) 132333
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chelidamic acid derivatives: Precursors to functionalized pyridyl
cryptands & functionalized metal ligands
Harry W. Gibson*, Terry L. Price Jr., Adam M.-P. Pederson, Zhenbin Niu,
Pothanagandhi Nellipalli
Department of Chemistry, Virginia Polytechnic Institute & State University, Virginia Tech, Blacksburg, Virginia, 24060, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyridyl cryptands, such as 12e16 formed from pyridine-2,6-dicarbonyl chloride (4) and crown ether diols
7e11, have been demonstrated to be excellent hosts for viologens (N,N0-dialkyl-4,40-bipyridinium salts, 2)
Received 28 April 2021
Received in revised form
2 July 2021
Accepted 5 July 2021
Available online 12 July 2021
with Ka values of ~104 to 106
M
ꢀ1 and thus are considered to be ideal building blocks for supramolecular
systems. However, in order to incorporate these host motifs into useful starting materials, functionali-
zation is required; in this article we describe syntheses of 23 new chelidamic acid (2,6-dicarboxy-4-
hydroxypyridine, 5) derivatives that can be used to prepare functional pyridyl cryptands and func-
tional metal ligands. The preparation and characterization of three new functionalized pyridyl cryptands
are also included.
Keywords:
Chelidamate
Pyridyl cryptand precursor
Metal ligand precursor
Host-guest chemistry
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
building blocks for supramolecular chemistry (Scheme 1, Table 1).
Recently a template method was reported to increase the cycliza-
The application of host-guest chemistry to supramolecular
chemistry requires powerful and specific interactions between the
two components to ensure efficient self-assembly processes [1e11].
A well-used host-guest motif is the interaction of crown ethers,
such as bis(m-phenylene)-32-crown-10 (1), with viologens (N,N0-
dialkyl-4,40-bipyridinium salts) 2, which afford association con-
stants (Ka) in the range 20e3333 Mꢀ1 [12,13]. Conversion of bis(m-
phenylene)-32-crown-10 (1) to cryptand 3 by incorporation of a
third ethyleneoxy arm increased Ka 100-fold to 6.1 x 104 Mꢀ1, totally
due to its preorganization, which reduced the entropic penalty [14].
Further, conversion of the crown ether diol 8 to pyridyl cryptand 13
(Scheme 1), thus introducing a nitrogen for interaction with the
viologen, by reaction with diacid chloride (4) increased the asso-
ciation constant by two more orders of magnitude to 5ꢁ 106 Mꢀ1
(Table 1) [15]. Therefore, other crown ethers have been converted
to their pyridyl cryptands, thus providing a family of more efficient
tion yields of the pyridyl cryptands dramatically [24]; this method
coupled with templation of the formation of dibenzo crown ethers
via the Wang-Pederson-Wessels protocol (using KPF6) [18,25,26]
allows efficient preparation of these powerful hosts at scale.
However, to be useful these cryptands need to possess functional
groups that allow them to be incorporated into well-designed,
larger building blocks. The present article describes approaches to
functional precursors to such cryptands, i. e., derivatives of cheli-
damic acid (5). Conveniently, there is a high-yielding (81%) litera-
ture procedure for the synthesis of chelidamic acid from acetone
and diethyl oxalate via aldol condensation to form chelidonic acid
(6), which is converted to 5 by reaction with ammonia [27]. The
hydroxyl group at the 4-position of chelidamic acid is ideal for
functionalization, given the wide range of reactions available for
hydroxyl moieties.
* Corresponding author.
E-mail address: hwgibson@vt.edu (H.W. Gibson).
https://doi.org/10.1016/j.tet.2021.132333
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

H.W. Gibson, T.L. Price Jr., A.M.-P. Pederson et al.
Tetrahedron 94 (2021) 132333
2. Results & discussion
20, in which the E isomer slightly predominated over the Z by
52:48%. The disappointing yields of these couplings, presumably
due to complexation of the Pd catalyst by the pyridine nitrogen, led
us to abandon this approach.
2.1. Heck cross coupling
Initial efforts focused on Heck coupling reactions [28]. Cheli-
damic acid was converted to the 4-bromo diesters 17a and 17b in
good yields (Scheme 2). 17a was subjected to Heck coupling first
with p-chloromethylstyrene to afford reactive monomer 18,
entirely in the E isomeric form of the stilbene-like double bond;
basic hydrolysis of the ester moieties and the chloromethyl group
yielded 19. Heck conditions with 17b and ethyl vinyl ether afforded
2.2. Williamson ether synthesis
The venerable, classic Williamson ether synthesis is an obvious
approach for general functionalization of chelidamic esters.
Therefore, dimethyl and diethyl chelidamates (21a and 21b) were
prepared [29].
Scheme 1. Syntheses of pyridyl cryptands from crown ether diols using pyridine-2,6-diarboxylic acid chloride.
2

H.W. Gibson, T.L. Price Jr., A.M.-P. Pederson et al.
Tetrahedron 94 (2021) 132333
Table 1
the N-alkylated product (25), respectively, as a result of the
tautomerism between the quinoidal and the aromatic forms of the
starting diester.
Association constants for crown ether and cryptand hosts with viologens 2a and 2b
in acetone at 22e25 ꢂC.
Host
Guest
Ka (mol/L)
Ref.
We reasoned that bulky esters would restrict the Williamson
reaction to the desired O-alkylated product. Therefore, diisopropyl
chelidamate (21c) was prepared [29] and subjected to the same
reaction conditions (Scheme 5). The sole product was the desired
O-alkylated product 26, which afforded the substituted diacid 27
upon basic hydrolysis. To demonstrate the usefulness of this reac-
tion, product 26 was elaborated to the secondary benzylic bromide
28, which was isolated as a mixture with an unknown minor
component. Nonetheless, when subjected to treatment as shown in
Scheme 6, the tetramethylpiperidine-N-oxide (TEMPO) derivative
29 was isolated.
With the alkylation reaction under control we moved forward
with other Williamson ether derivatizations of diisopropyl cheli-
damate 21c.
Scheme 7 displays reactions of diisopropyl chelidamate (21c)
with other electrophiles with chloride leaving groups. Similarly,
Scheme 8 summarizes reactions of 21c with alkyl bromides and
hydrolysis of the diesters to the diacids. Bromo compounds 33 and
34 (Scheme 8) were reported earlier [31]. The C10 dimer ester 43
and derived diacid 44 (Scheme 8) were also reported earlier as
building blocks for supramolecular polymers [32].
Scheme 9 summarizes reactions of 21c with electrophiles with
tosylate leaving groups; the dimeric chelidamate 47 and the cor-
responding diacid 48 were reported earlier as building blocks for
supramolecular polymers [32]. The target molecule of the reaction
between 21c and p-bis(tosyloxyethoxy)benzene at 2:1 stoichiom-
etry, respectively, was 47, but 45 was isolated as the main product.
The reaction of 21c (2 eq.) with the ditosylate (1 eq.) in the presence
of potassium carbonate was executed using acetonitrile as the
solvent and also using acetone. Acetone gave a 4:1 ratio of 45:47 as
described in the Experimental section, but with acetonitrile the
product ratio was 1:>99 45:47 [32]. Acetone retarded the reaction
speed vs. acetonitrile, allowing temporal control over mono- or di-
additions. Note that the yields of these reactions are not optimized;
indeed, some of the low yields can be attributed to small reaction
scales and some to solubility issues.
1
3
8
13
7
12
12
9
14
14
10
15
15
11
16
2a
2a
2a
2a
2a
2a
2b
2a
2a
2b
760
[16]
[14]
[14]
[15]
[17]
[18]
[18]
6.1 x 104
5.7 x 102
5.0 x 106
1.1 x 103
2.0 x 105
1.0 x 105
NAa
2.49 x 105
6.70 x 104
NAa
[19]
[19]
2a
2b
5.11 x 104
8.08 x 103
NAb
[19]
[19]
2b
1.0 x 104
[20]
a
NA ¼ not available in the literature.
b
NA ¼ probably complicated by ion pairing effects [21e23].
Initially using the dimethyl ester 21a we successfully introduced
the aldehyde (formyl) group into the chelidamic acid residue as
shown in Scheme 3. Using cesium carbonate as the base and DMF as
the solvent, preparation of the desired ether 22 proceeded in high
yield. Basic hydrolysis afforded the corresponding diacid 23;
interestingly the good yield indicated that the possible Cannizzaro
side reaction [30] induced by the strongly basic conditions did not
interfere.
Then diethyl ester 21b was subjected to Williamson reaction
conditions with p-chloromethylstyrene (Scheme 4). The
substituted styrene product, obtained in modest yield, consisted of
two isomers in 80:20 ratio, the desired O-alkylated isomer (24) and
2.3. Potential applications
The aldehyde derivatives 22, 23, 32, 41 and 42 were prepared as
Scheme 2. Heck coupling reactions starting with chelidamic acid: a) PBr3, b) CH3OH (91%); c) CH3CH2OH (95%); d) p-chloromethylstyrene/Pd(OAc)2/P(C6H5)3/Na2CO3/DMF (14%); e)
KOH/THF-H2O (71%); f) ethyl vinyl ether/Pd(OAc)2/P(C6H5)3/K2CO3/DMF (35%).
3

H.W. Gibson, T.L. Price Jr., A.M.-P. Pederson et al.
Tetrahedron 94 (2021) 132333
Scheme 3. Synthesis of dimethyl chelidamate formyl derivatives: a) Cs2CO3/DMF/90 ꢂC (88%); b) KOH/H2O/reflux (80%).
chain reaction terminators in ring opening metathesis polymeri-
zations (ROMP) [33e35]; they will react with the growing poly-
mers’ metal carbene end groups to produce macromolecules with
chelidamate functions at the ends for further supramolecular
construction, either via conversion to active metal complexes
[29,36e38] (including chirality [38e40]) or to cryptands tailored
for specific supramolecular interactions.
The secondary bromo derivative 28 is an initiator for atom
transfer radical polymerization (ATRP) [41] of vinyl monomers. The
corresponding TEMPO compound 29 is an initiator for nitroxide
mediated radical polymerization (NMP) [42] of vinyl monomers.
The products of these two types of polymerizations will bear che-
lidamate end groups that could be used to form active metal ligands
[29,36e40], as noted above, or cryptands tailored for specific su-
pramolecular interactions.
The halide functionalized compounds 18, 30, 33e38 were
designed as substrates for Heck [28], Sonogshira [43] and related
Suzuki couplings [44]. 18 could also be a substrate for further
Williamson ether syntheses.
The styryl monomers 24, 26 and 27 are obvious targets for vinyl
Scheme 4. Williamson ether synthesis with diethyl chelidamate: a) p-chloromethylstyrene/K2CO3/acetone, reflux (57%).
Scheme 5. Williamson ether synthesis with diisopropyl chelidamate: a) p-chloromethylstyrene/K2CO3/acetone, reflux (64%); b) KOH/THF-H2O/rt; c) HCl (97%).
Scheme 6. Conversion of styrene 26 to bromide 28 and thence to TEMPO derivative 29: a) PBr3 @ SiO2/CH2Cl2, rt, 2h (86%, a mixture); b) TEMPO/Cu powder/Cu(OTf)2/PMDETA/
benzene/reflux (57%).
4

H.W. Gibson, T.L. Price Jr., A.M.-P. Pederson et al.
Tetrahedron 94 (2021) 132333
Scheme 7. Williamson ether synthesis with diisopropyl chelidamate (21c) and electrophiles with benzylic chloride leaving groups: a) p-bis(chloromethyl)benzene/K2CO3/acetone,
reflux (15%); b) KOH/THF-H2O/rt; c) HCl (97%); d) p-(p’-chloromethylbenzyloxy)benzaldehyde/K2CO3/acetone/reflux (59%).
Scheme 8. Chelidamic acid derivatives prepared by Williamson ether synthesis from diisopropyl chelidamate (21c) and electrophiles with bromide leaving groups: alkyl bromide/
K2CO3/acetone/reflux. Hydrolyses: KOH/THF-H2O/rt.
5

H.W. Gibson, T.L. Price Jr., A.M.-P. Pederson et al.
Tetrahedron 94 (2021) 132333
Scheme 9. Chelidamic acid derivatives prepared by Williamson ether syntheses from diisopropyl chelidamate (21c) and electrophiles with tosylate leaving groups: tosylate/K2CO3/
acetone/reflux. Hydrolyses: KOH/THF-H2O/rt.
polymerization via free radical and cationic techniques.
3. Conclusions
The pyridyl functionalized systems 39 and 40 were envisioned
to be useful because of the additional ligand binding site
[29,36e40] they provide as well as their ability to be protonated.
We reported several derivatizations of chelidamic acid to pro-
duce useful precursors to pyridyl cryptands and/or metal ligands
[29,36e40]. Heck cross coupling under unoptimized conditions
afforded only low yields of products. Williamson ether conditions
with variety of electrophiles efficiently provide a wide range of
functionalized derivatives. In all, here we reported 23 new de-
rivatives of chelidamic acid and three new pyridyl cryptands.
2.4. Formation of new pyridyl cryptands
The conversion of these chelidamic acid derivatives to cryptands
is illustrated by the following examples, which involve pseudo-high
dilution syntheses, inasmuch as the present work was done prior to
the development of the template synthetic approach to cryptands
[24]. Known [45] 4-benzyloxypyridine-2,6-dicarbonyl chloride (49)
underwent cyclization with cis-dibenzo30-crown-10 diol (7) [18],
yielding cryptand 50 (Scheme 10); attempts to deprotect the
phenolic functionality by hydrogenolysis led to an unknown
mixture of the desired phenol as a minor component, apparently
the result of cleavage of the ester moieties. Formyl functionalized
cryptand 51 resulted from cis-dibenzo-30-crown-10 diol (7) [18]
and chelidamate 23 (Scheme 11). These cyclization yields could no
doubt be improved by using the template method reported in the
meantime [24].
And finally the new diamide cryptand 54 resulted from reaction
of known diamine 52 [prepared from chelidamic acid (5)] [46] and
known dibenzo-30-crown-10 diacid chloride 53 [47] (Scheme 12).
The complexation properties of new cryptands 50, 51 and 54
were not examined in this work.
Attempts to remove the benzyl protecting group from 50 by
hydrogenolysis to form the phenolic cryptand were futile; it
appeared that the ester moieties were cleaved under these
conditions.
4. Experimental section
4.1. General
1H NMR spectra were obtained on JEOL Eclipse-500, Bruker-500
and Agilent-NMR-vnmrs400 spectrometers; signal assignments
were made using COSY. 13C NMR spectra were collected at 126, 126
and 101 MHz on these instruments, respectively. High resolution
electrospray mass spectra (HR ESI MS) were obtained using an
Agilent HP121 or HP921 LC-ESI-TOF system with acetonitrile as
solvent; fast atom bombardment (FAB) spectra were obtained in
both low and high resolution modes (LR and HR, respectively) using
a JEOL Model HX 110 Dual Focusing Mass Spectrometer with xenon
gas for ionization; the samples were mixed in nitrobenzoic acid/
poly(ethylene glycol) (NBA/PEG). Unless noted starting materials
were obtained from commercial sources and used as received. The
following compounds were made in accordance with literature
procedures; yields similar to those reported were achieved: 5 [27],
di(4-hydroxymethylbenzo)-30-crown-10 (7) [18], 4-bromoesters
17a and 17b [48], dialkyl chlidamates (21ae21c) [29], p-iodoben-
zyl bromide [49], p-bis(20-tosyloxyethoxy)benzene [50], p-(20-
Scheme 10. Synthesis of new benzyloxy cryptand 50 from 4-benzyloxypyridine-2,6-dicarbonyl chloride (49) a) cis-dibenzo-30-crown-10 diol (7)/pyridine/dichloromethane/syringe
pump addition/pseudo-high dilution (42%).
6

H.W. Gibson, T.L. Price Jr., A.M.-P. Pederson et al.
Tetrahedron 94 (2021) 132333
Scheme 11. Synthesis of new formyl functionalized cryptand 51 from diacid 23: a) SOCl2/reflux; b) cis-dibenzo-30-crown-10 diol (7)/pyridine/dichloromethane/syringe pump
addition/pseudo-high dilution (23%).
Scheme 12. Synthesis of new diamide cryptand 54 from 4-benzyloxypyridine-2,6-diamine (52) and cis-dibenzo-30-crown-10 dicarbonyl chloride (53): a) pyridine/dichloro-
methane/pyridinium trifluoromethylsulfonylimide template [24] (21%).
bromoethoxy)benzaldehyde [51], p-(p’-chloromethylbenzyloxy)
benzaldehyde [52], 4-benzyloxypyridine-2,6-dicarbonyl chloride
(52) [45] and di(4-chlorocarbonylbenzo)-30-crown-10 (53) [47].
9.41 mmol), PPh3 (156 mg, 0.595 mmol), and ethyl vinyl ether
(1.0 mL, 10 mmol). The reaction mixture was stirred under nitrogen
at 90 ꢂC for 19 h. Solvent was removed by rotary evaporation and
the crude material was dissolved in chloroform. The solution was
washed with 1 M HCl (x3) and water (x3), followed by drying over
Na2SO4. Filtration and removal of the solvent provided a material
which was purified by passing through a silica column, eluting with
hexanes:ethyl acetate (EA) 1:1, to give a mixture of E- and Z-iso-
mers, the latter slightly predominating 52:48%; 0.74 g (35%), mp
(E-)
Dimethyl
4-(p’-chloromethylstyryl)pyridine-2,6-
dicarboxylate (18). Dimethyl 4-bromopyridine-2,6-dicarboxylate
(17a) (0.83g, 3.0 mmol), Pd(OAc)2 (22.2 mg, 0.0989 mmol), PPh3
(63.5 mg, 0.242 mmol), and Na2CO3 (0.45 g, 4.2 mmol) were added
to a flask containing a magnetic stir bar. The solvent, DMF (80 mL),
and p-vinylbenzyl chloride (0.60 mL, 4.3 mmol) were added to the
flask once an oil bath had been preheated to 90 ꢂC. The reaction
mixture was allowed to stir at 90 ꢂC under nitrogen for 60 h. A
portion of solvent was removed by rotary evaporation and the
remaining mixture was dissolved in chloroform; the mixture was
washed with 1 M HCl (x2), water (x3), and dried over Na2SO4. After
filtration and evaporation of the solvent, a minimal amount of
chloroform was used to dissolve the product and it was precipitated
into ether (~100 times the volume of chloroform): a yellow tinted
solid, 146.5 mg (14%), mp 175.0e177.0 ꢂC (dec). 1H NMR (400 MHz,
48.2e55.7 ꢂC. 1H NMR (500 MHz, CDCl3)
d 8.40 (s, 2.0H), 8.04 (s,
1.8H), 7.39 (d, J ¼ 13 Hz, 0.94H), 6.54 (d, J ¼ 7 Hz, 1.0H), 5.82 (d,
J ¼ 13 Hz, 0.88H), 5.31 (d, J ¼ 7 Hz, 1.0H), 4.46 (m, 8H), 4.11 (q,
J ¼ 7 Hz, 2.0H), 3.99 (q, J ¼ 7 Hz, 1.7H), 1.35e1.50 (m, 18.5H). 13C
NMR (126 MHz, CDCl3)
d 165.37, 165.22, 153.56, 152.85, 148.83,
148.66, 147.75, 146.18, 126.36, 123.29, 102.87, 102.16, 70.52, 66.79,
62.37, 62.22, 15.46, 14.80, 14.31 (20 peaks expected, 19 peaks
observed). HR ESI MS: calc. C15H20NO5 [MþH]: 294.1366, found m/z
294.1301 (error ꢀ2.2 ppm); calc. for C30H38N2O10Na [2 MþNa]þ: m/
z 609.2419, found: m/z 609.2364 (error ꢀ8.9 ppm).
CDCl3)
d
8.38 (s, 2H), 7.62e7.41 (m, 5H), 7.14 (d, J ¼ 16 Hz, 1H), 4.62
(s, 2H), 4.05 (s, 6H). 13C NMR (126 MHz, CDCl3)
d
165.38, 148.85,
p-(40-bromobutoxy)benzaldehyde. K2CO3 (5.75g, 38.0 mmol),
p-hydroxybenzaldehyde (4.93 g, 38.0 mmol), and 1,4-
dibromobutane (41.00 g, 190 mmol, distilled) were added to
acetone (240 mL) and the mixture was refluxed for 6 h under N2.
The reaction mixture was cooled to rt and solvent was removed.
H2O (100 mL), 2 M HCl (100 mL), and CH2Cl2 (400 mL) were added
and mixed. The organic phase was collected and washed with 10%
Na2CO3 (x2). The organic phase was dried with Na2SO4, filtered, and
concentrated to an oil, which was subjected to silica gel chroma-
tography. The excess dibromobutane was eluted with hexanes and
the product was eluted with diethyl ether as a pale-yellow oil
(5.16 g, 68%), reported [53] mp 32e34 ꢂC. 1H NMR (CDCl3, 400 MHz)
147.59, 138.78, 135.68, 135.11, 129.34, 128.98, 127.77, 125.05, 53.38,
45.83 (12 peaks expected and 12 peaks found). HR ESI MS: calc. for
C
18H17NO4Cl [MþH]þ: m/z 346.0841; found: m/z 346.0860 (error
5.7 ppm).
General procedure 1: (E- & Z-) 4-(p’-hydroxymethylstyryl)
pyridine-2,6-dicarboxylic acid (19). 18 (187.8 mg, 0.5431 mmol)
was dissolved in THF (50 mL) and a solution of 10 wt % aq. KOH
(30 mL) was added to the stirred solution. The solution was stirred
for 12 h and THF was removed by rotary evaporation. The
remaining aqueous solution was acidified to pH 1 and the white
precipitate was collected by filtration: 115.6 mg (71%), mp
85.6e91.4 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d
8.40 (s, 2H), 7.78 (d,
d
: 9.89 (s, 1H), 7.84 (m, 2 H), 6.99 (m, 2H), 4.09 (t, J ¼ 6 Hz, 2H), 3.50
J ¼ 16 Hz, 1H), 7.69 (d, J ¼ 8 Hz, 2H), 7.46 (d, J ¼ 16 Hz, 1H), 7.37 (d,
(t, J ¼ 10 Hz, 2H),1.95e2.13 (m, 4H). LR FAB MS (NBA): m/z 257,100%
[M(79Br)þH]þ; 258, 28% [MþHþ1]þ; 259, 87% [M(81Br)þH and
M(79Br)þHþ2]þ; 260, 15% [M(81Br)þH and M(79Br)þHþ3]þ.
J ¼ 8 Hz, 2H), 4.53 (s, 2H). 13C NMR (126 MHz, DMSO-d6, major
signals)
d 166.15, 149.28, 148.33, 144.35, 135.64, 134.93, 127.84,
127.37, 124.60 (two closely spaced peaks), 63.18 (11 peaks expected
and 11 peaks found). HR ESI MS: calc. for C16H14O5N [MþH]þ: m/z
300.0867; found: m/z 300.0872 (error ꢀ2 ppm).
Dimethyl
4-[4’-(p”-formylphenoxy)butoxy]pyridine-2,6-
dicarboxylate (22). Dimethyl chelidamate (21a) (1.48 g,
7.1 mmol), p-(40-bromobutoxy)benzaldehyde (2.97 g, 11.0 mmol),
and Cs2CO3 (2.88 g, 9.0 mmol) were stirred in DMF (20 mL) at 85 ꢂC
under nitrogen for 4 h. The solvent was removed and the reaction
mixture was partitioned in H2O/ethyl acetate. The aqueous phase
was extracted with EA (x3). The combined organic phase was
(E-
&
Z-)
Diethyl
4-(2′-ethoxyvinyl)pyridine-2,6-
dicarboxylate (20). To a flask containing DMF (100 mL) were
added Pd(OAc)2 (57.5 mg, 0.256 mmol), diethyl 4-bromopyridine-
2,6-dicarboxylate (17b, 2.16 g, 7.88 mmol), K2CO3 (1.30 g,
7

H.W. Gibson, T.L. Price Jr., A.M.-P. Pederson et al.
Tetrahedron 94 (2021) 132333
washed with 10% Na2CO3, H2O (x2) and sat. NaCl and then dried
with Na2SO4; the solution was filtered, and the solvent was evap-
orated. The product was isolated via column chromatography (sil-
ica, 3:2 EA:hexanes): 2.42 g (88%), mp 89.9e91.5 ꢂC. 1H NMR (CDCl3,
(d, J ¼ 18 Hz, 1H), 5.34 (s, 2H), 5.26 (d, J ¼ 11 Hz, 1H). 13C NMR
(101 MHz, DMSO-d6) d 167.07, 165.97, 150.45, 137.76, 136.88, 135.85,
128.83, 127.00, 115.40, 114.68, 70.54 (11 peaks expected, 11 peaks
found). HR ESI MS: calc. for C16H14O5N [MþH]þ: m/z 300.0866;
found: m/z 300.0864 (error 0.7 ppm).
400 MHz)
d
: 9.95 (s, 1H), 7.85 (d, J ¼ 8 Hz, 2H), 7.81 (s, 2H), 7.00 (d,
J ¼ 8 Hz, 2H), 4.25 (t, J ¼ 4 Hz, 2H), 4.16 (t, J ¼ 4 Hz, 2H), 4.02 (s, 6H),
2.07 (m, 4H). LR FAB MS (NBA): m/z 388.14, 100% [22 þ H]þ; 389.14,
20% [22 þ H þ 1]þ. HR FAB MS (PEG): m/z 388.1376 [22þH]þ, calcd.
for C20H22O7 388.1396, error 5.2 ppm.
Diisopropyl
4-[p’-(100-bromoethyl)benzyloxy]pyridine-2,6-
dicarboxylate (28). This procedure follows that applied to sty-
rene itself [54]. To a flask containing silica (2.20 g) were added
diisopropyl 4-(p-vinylbenzyloxy)pyridine-2,6-dicarboxylate (29,
0.383 g, 0.998 mmol) and dicloromethane (DCM) (10 mL) with
magnetic stirring under nitrogen. PBr3 (0.08 mL, 0.85 mmol) was
dissolved in DCM (1 mL) and added dropwise to the flask. After the
addition was complete, the flask was allowed to stir for 2 h. The
mixture was filtered and the filtrate was washed with aq. NaHCO3
(x3), saturated aq. NaCl (x2) and dried over Na2SO4. Filtration and
rotary evaporation provided the product: 400 mg (86%), white
4-[4’-(p”-Formylphenoxy)butoxy]pyridine-2,6-dicarboxylate
(23). Diester 22 (3.67 g, 9.47 mmol) was suspended in stirring EtOH
at 0 ꢂC. Aqueous KOH (3.20 g, 57.0 mmol) was added dropwise and
the mixture was stirred for 2 h and warmed to rt. The pH was
adjusted to <2 and 23 precipitated as a white solid (2.72 g, 80%). 1H
NMR (DMSO-d6, 400 MHz)
d
: 9.85 (s, 1H), 7.84 (d, J ¼ 8 Hz, 2H), 7.69
(s, 2H), 7.11 (d, J ¼ 8 Hz, 2H), 4.29 (m, 2H), 4.16 (m, 2H), 1.91 (m, 4H).
LR FABMS (NBA): m/z 238.8, 100% [23eOC6H4CHO]þ; 239.8, 15%
[23eOC6H4CHOþ1]þ; 273, 10% [23e2 CO2]þ; 273, <5% [23e2
CO2þ1]þ; 360.9, 50% [23þH]þ; 361.9, 10% [23þHþ1]þ. HR FAB MS:
m/z 360.1077 [23 þ H]þ, calcd. for C18H18NO7: 360.1039, error
1.8 ppm.
solid, mp 244.1e246.0 ꢂC (dec). 1H NMR (500 MHz, CDCl3)
d 7.80 (s,
2H), 7.49 (d, J ¼ 8 Hz, 2H), 7.41 (m, 4H), 7.36 (d, J ¼ 8 Hz, 2H, 7.09 (s,
3H), 5.32e5.24 (m, 6H), 5.19 (s, 2H), 5.18 (q, J ¼ 7 Hz, 2H), 4.47 (s,
1H), 2.04 (dd, J ¼ 5, 5 Hz, 3H), 1.41 (d, J ¼ 7 Hz, 6H), 1.39 (d, J ¼ 5,
12H). 13C NMR (126 MHz, CDCl3)
d 166.38, 164.09, 150.67, 143.85,
Diethyl 4-(p’-vinylbenzyloxy)pyridine-2,6-dicarboxylate (24)
and minor product diethyl 4-oxo-N-(p’-vinylbenzyl)-1,4-
dihydropyridine-2,6-dicarboxylate (25). To a flask containing
acetone (100 mL) with a magnetic stir bar were added diethyl
chelidamate (21b, 1.64 g, 6.86 mmol), p-vinylbenzyl chloride
(1.5 mL, 11 mmol) and K2CO3 (1.44 g, 10.4 mmol). The mixture was
held at reflux under nitrogen for 16 h, after which solvent was
removed by rotary evaporation and the crude material was dis-
solved in chloroform and washed with 1 M HCl (x3), saturated aq.
NaCl (x3) and dried over MgSO4. The solution was filtered and the
solvent was removed by rotary evaporation to give the product;
2.18 g, (57%), white solid, mp 64.2e70.6 ꢂC. 1H NMR (500 MHz,
143.85, 134.94, 129.38, 128.13, 127.35, 127.30, 114.34, 70.22, 48.67,
32.84, 26.74, 21.81 (13 peaks expected and 16 peaks found; 3 extra
aromatic peaks found). On the basis of the 1H and 13C NMR spectra,
the product was believed to be a mixture of the desired compound
and another compound or compounds).
Diisopropyl 4-{p’-[1”-(2000,2000,6000,6000-tetramethylpiperidin-N-
oxy)ethyl]benzyloxy}-pyridine-2,6-dicarboxylate (29). To
a
round bottom flask containing benzene (10 mL) were added copper
(II) trifluoromethanesulfonate (8.9 mg, 0.025 mmol), copper pow-
der (48.2 mg, 0.758 mmol), TEMPO (0.149 g, 0.952 mmol), the
impure diisopropyl 4-[p-(10-bromoethyl)benzyloxy]pyridine-2,6-
dicarboxylate (28, 0.287 g, 0.618 mmol), and N,N,N0,N00,N00-pen-
tamethyldiethylenetriamine (PMDETA) (0.02 mL, 0.1 mmol) with
magnetic stirring under nitrogen. The mixture was held at reflux for
30 h, diluted with DCM, filtered through Celite p545®, and the
solvent was removed by rotary evaporation. The residue was pu-
rified using column chromatography (neutral alumina, eluting with
DCM:MeOH 99:1); the product eluted as the first fraction: 0.1893 g
(57%), white solid, mp 113.1e116.5 ꢂC. 1H NMR (500 MHz, CDCl3)
CDCl3, major signals only)
d
7.85 (s, 2H), 7.45 (d, J ¼ 8 Hz, 2H), 7.39
(d, J ¼ 8 Hz, 2H), 6.72 (dd, J ¼ 18, 11 Hz, 1H), 5.78 (d, J ¼ 18 Hz, 1H),
5.29 (d, J ¼ 11 Hz, 1H), 5.20 (s, 2H), 4.46 (q, J ¼ 7 Hz, 4H), 1.44 (t,
J ¼ 7 Hz, 6H). Integrations of major and minor signals demonstrated
that the product consisted of 80% O-alkylated isomer and 20% N-
alkylated isomer. 13C NMR (126 MHz, CDCl3)
d 166.59 (s), 164.71,
150.29, 138.10, 136.18, 134.14, 128.00, 126.66, 114.63, 114.33, 70.53,
62.43, 14.20 [26 peaks expected and 26 peaks found, 13 for O-
alkylation (80%) and 13 for N-alkylation (20%)]. HR ESI MS: calc. for
d
7.81 (s, 2H), 7.40e7.35 (m, 4H), 5.34e5.24 (m, 2H), 5.20 (s, 2H),
4.80 (q, J ¼ 6 Hz, 1H), 1.52e1.23 (m, 23H), 1.16 (s, 4H), 1.02 (s, 3H),
0.63 (s, 3H). 13C NMR (126 MHz, CDCl3)
166.53, 164.12, 150.62,
C
20H21NO5 [MþH]þ: m/z 356.1492; found: m/z 356.1463 (error
d
8.1 ppm).
146.55, 133.20, 127.66, 127.09, 114.41, 82.78, 70.75, 70.11, 59.69,
40.35, 34.45, 34.17, 23.52, 21.82, 20.34,17.21 (19 peaks expected and
19 peaks found). HR ESI MS: calc. for C31H45O6N2 [MþH]þ: m/z
541.3272; found: m/z 541.3283 (error ꢀ2.0 ppm).
Diisopropyl 4-(p’-vinylbenzyloxy)pyridine-2,6-dicarboxylate
(26). To a flask containing acetone (200 mL) were added p-vinyl-
benzyl chloride (7.0 mL, 50 mmol), diisopropyl chelidamate (21c,
8.65 g, 32.4 mmol) and K2CO3 (7.4 g, 54 mmol). The mixture was
held at reflux under nitrogen for 22 h with magnetic stirring and
filtered through Celite p545®. The solvent was removed by rotary
evaporation. The crude material was triturated with hexanes and
the remaining solid was collected: 7.98 g (64%), mp 96.2e98.1 ꢂC.
Diisopropyl
4-(p’-chloromethylbenzyloxy)pyridine-2,6-
dicarboxylate (30). To a round bottom flask containing acetone
(300 mL) were added p-bis(chloromethyl)benzene (3.57 g,
20.4 mmol) and K2CO3 (3.08 g, 22.3 mmol) with magnetic stirring.
Diisopropyl chelidamate (21c, 0.91 g, 3.4 mmol) was dissolved in
acetone and placed in an addition funnel attached to the reaction
flask under nitrogen. The reaction flask was held at reflux and the
solution of 21c was added dropwise. After the addition was com-
plete, the mixture was kept at reflux for 36 h, filtered through Celite
p545® and the solvent was removed by rotary evaporation. The
crude material was triturated with hexanes and the solid was
collected via filtration and purified on a silica column, eluting with
DCM: 0.21 g (15%), mp 141.1e143.7 ꢂC. 1H NMR (400 MHz, CDCl3)
1H NMR (500 MHz, CDCl3)
d
7.80 (s, 2H), 7.45 (d, J ¼ 8 Hz, 2H), 7.39
(d, J ¼ 8 Hz, 2H), 6.72 (dd, J ¼ 18, 11 Hz, 1H), 5.78 (d, J ¼ 18 Hz, 1H),
5.36e5.22 (m, 3H), 5.19 (s, 2H), 1.41 (d, J ¼ 6 Hz, 12H). 13C NMR
(126 MHz, CDCl3)
d 166.53, 164.20, 150.72, 138.18, 136.27, 134.30,
128.15,126.73,114.81,114.46, 70.58, 70.26, 21.89 (13 peaks expected
and 13 peaks found). HR ESI MS: calc. for C22H26NO5 [MþH]þ: m/z
384.1806; found: m/z 384.1798 (error 2 ppm).
4-(p’-Vinylbenzyloxy)pyridine-2,6-dicarboxylic acid (27).
General procedure 1 (above) was used with styrene chelidamic
ester 26 (0.24 g, 0.63 mmol), THF (15 mL) and 10% wt. aqueous KOH
d
7.80 (s, 2H), 7.43 (s, 4H), 5.33e5.22 (m, 2H), 5.20 (s, 2H), 4.59 (s,
2H), 1.41 (d, J ¼ 6 Hz, 12H). 13C NMR (101 MHz, CDCl3)
d 166.56,
(50 mL) to produce 0.16
140.2e144.2 ꢂC. 1H NMR (400 MHz, DMSO-d6)
J ¼ 8 Hz, 2H), 7.44 (d, J ¼ 8 Hz, 2H), 6.73 (dd, J ¼ 18, 11 Hz, 1H), 5.84
g
(86%) of colorless solid, mp
164.27, 150.85, 138.25, 135.28, 129.38, 128.42, 114.67, 70.54, 70.31,
45.91, 22.04 (12 peaks expected and 12 peaks found). HR ESI MS:
calc. for C21H25NO5Cl [MþH]þ: m/z 406.1416; found: m/z 406.1405
d
7.77 (s, 2H), 7.50 (d,
8

H.W. Gibson, T.L. Price Jr., A.M.-P. Pederson et al.
Tetrahedron 94 (2021) 132333
(error 2.7 ppm).
peaks found; also very small impurity signals possibly due to
product instability. Since the product was an intermediate, it was
used without further purification). HR ESI MS: calc. for C14H12OBr
[MBr]þ: m/z 275.0067; found: m/z 275.0065 (error ꢀ0.7 ppm).
Diisopropyl 4-[p’-(p”-bromobenzyloxy)benzyloxy]pyridine-
2,6-dicarboxylate (37). To a round bottom flask containing acetone
(200 mL) were added diisopropyl chelidamate (21c, 5.50 g,
20.6 mmol), K2CO3 (4.00 g, 28.9 mmol), and p-(p’- bromomethyl-
phenoxymethyl)bromobenzene (7.91 g, 22 mmol) with magnetic
stirring under nitrogen. The reaction mixture was held at reflux for
19 h, followed by filtration through Celite p545® and removal of the
solvent via rotary evaporation. The solid was triturated with boiling
hexanes and filtered: a white solid, 10.51 g (94%), mp 90.4e92.6 ꢂC.
4-(p’-Hydroxymethylbenzyloxy)pyridine-2,6-dicarboxylic
acid (31). General procedure 1 was used with diisopropyl 4-(p’-
chloromethylbenzyloxy)pyridine-2,6-dicarboxylate (33, 214.1 mg,
0.5275 mmol), 10% wt. aq. KOH (30 mL) and THF (30 mL) to produce
23.7 mg (15%) of colorless solid, mp 127.0e134.3 ꢂC. 1H NMR
(500 MHz, DMSO-d6)
d
7.81 (s, 2H), 7.50 (bs, 4H), 5.39 (s, 2H), 4.78
166.36, 165.24, 149.78,
(s, 2H). 13C NMR (126 MHz, DMSO-d6)
d
137.66, 135.73, 129.05, 128.05, 113.91, 69.70, 45.77 (10 peaks ex-
pected and 10 peaks found). HR ESI MS: calc. for C15H13O6N [MH]-:
m/z 302.0670; found: m/z 302.0681 (error 3.6 ppm).
Diisopropyl 4-[p’-(p”-formylphenoxymethyl)benzyloxy]pyri-
dine-2,6-dicarboxylate (32). To a flask containing acetone (60 mL)
were added p-(p’-chloromethylbenzyloxy)benzaldehyde (0.88 g,
3.4 mmol), diisopropyl chelidamate (21c, 0.87 g, 3.3 mmol) and
K2CO3 (0.90 g, 6.5 mmol) with magnetic stirring under nitrogen.
The reaction mixture was held at reflux for 31 h, cooled to room
temperature, passed through Celite p545® and evaporated. The
product was obtained by triturating the crude material with hex-
anes: a yellow solid, 0.94 g (59%), mp 124.4e127.4 ꢂC. 1H NMR
1H NMR (400 MHz, CDCl3)
d
7.80 (s, 2H), 7.51 (d, J ¼ 8 Hz, 2H), 7.36
(d, J ¼ 9 Hz, 2H), 7.31 (d, J ¼ 8 Hz, 2H), 6.98 (d, J ¼ 9 Hz, 2H), 5.28
(hept, J ¼ 6 Hz, 2H), 5.13 (s, 2H), 5.04 (s, 2H), 1.42 (d, J ¼ 6 Hz, 12H).
13C NMR (101 MHz, CDCl3) 166.68, 164.35, 159.09, 150.82, 135.95,
132.02, 129.94, 129.25, 127.58, 122.20, 115.37, 114.63, 70.71, 70.42,
69.52, 22.04 (16 peaks expected and 16 peaks found). HR ESI MS:
calc. for C27H28O6NBrNa [MþNa]þ: m/z 564.0992; found: m/z
564.0983 (error ꢀ2 ppm).
(500 MHz, CDCl3)
d
9.90 (s, 1H), 7.85 (d, J ¼ 9 Hz, 2H), 7.82 (s, 2H),
7.49 (s, 4H), 7.08 (d, J ¼ 9 Hz, 2H), 5.29 (hept, J ¼ 6 Hz, 2H), 5.23 (s,
4-[p’-(p”-Bromobenzyloxy)benzyloxy]pyridine-2,6-
dicarboxylic acid (38). General procedure 1 was used with diiso-
2H), 5.18 (s, 2H), 1.42 (d, J ¼ 6 Hz, 12H). 13C NMR (126 MHz, CDCl3)
d
190.74, 166.38, 164.10, 163.54, 150.68, 136.62, 135.00, 132.02,
propyl
4-[p’-(p”-bromobenzyloxy)benzyloxy]pyridine-2,6-
130.28, 128.15, 127.89, 115.14, 114.34, 70.32, 70.22, 69.81, 21.81 (17
peaks expected and 17 peaks found). HR ESI MS: calc. for C28H30NO7
[MþH]þ: m/z 492.2017; found: m/z 492.2029 (error 2.4 ppm).
Diisopropyl 4-(p’-iodobenzyloxy)pyridine-2,6-dicarboxylate
(35). To a round bottom flask containing acetone (75 mL) were
added p-iodobenzyl bromide (0.55 g, 1.9 mmol), diisopropyl che-
lidamate (21c, 0.59 g, 2.2 mmol), and K2CO3 (0.52 g, 3.8 mmol). The
mixture was placed under nitrogen and held at reflux for 1 day,
after which it was allowed to cool and filtered through Celite
p545®. The solvent was removed by rotary evaporation and the
crude material was purified via flash column chromatography
(silica, eluting with 100% DCM to 100% EA; product eluted in 10%
EA): 0.75 g (84%), white solid, mp 187.3e189.8 ꢂC. 1H NMR
dicarboxylate (37, 1.21 g, 2.23 mmol), 10% wt. aq. KOH (20 mL)
and THF (30 mL) to produce a white solid, 1.01 g (99%), mp
189.1e192.3 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d 7.77 (s, 2H), 7.58 (d,
J ¼ 8 Hz, 2H), 7.42 (d, J ¼ 8 Hz, 2H), 7.41 (d, J ¼ 8 Hz, 2H), 7.03 (d,
J ¼ 8 Hz, 2H), 5.27 (s, 2H), 5.10 (s, 2H). 13C NMR (126 MHz, DMSO-d6)
d
167.05, 165.87, 158.74, 150.30, 137.03, 131.93, 130.38 (two closely
spaced peaks), 128.37, 121.51, 115.44, 114.49, 70.51, 68.95 (14 peaks
expected and 14 peaks found). HR ESI MS: calc. for C21H17O6NBr
[MþH]þ: m/z 458.0234; found: m/z 458.0238 (error 0.9 ppm).
Diisopropyl
4-(4′-pyridylmethoxy)pyridine-2,6-
dicarboxylate (39). Diisopropyl chelidamate (21c, 1.80 g,
6.73 mmol), 4-bromomethylpyridine hydrobromide (2.00 g,
7.91 mmol), and K2CO3 (2.50 g, 18.1 mmol) were combined in a
round bottom flask with acetone (60 mL) under nitrogen and held
at reflux for 4 days. After cooling, the mixture was filtered through
Celite p545® and the solvent was removed by rotary evaporation.
The product was isolated by flash column chromatography on silica,
eluting with DCM to EA: 0.39 g (16%) of colorless solid, mp
(500 MHz, CDCl3)
J ¼ 8 Hz, 2H), 5.29 (hept, J ¼ 6 Hz, 2H), 5.15 (s, 2H), 1.43 (d, J ¼ 6 Hz,
13H). 13C NMR (126 MHz, CDCl3)
166.23, 164.06, 150.75, 138.00,
d
7.79 (s, 2H), 7.76 (d, J ¼ 8 Hz, 2H), 7.19 (d,
d
134.52, 129.50, 114.26, 94.42, 70.21, 69.99, 21.81 (11peaks expected
and 11 peaks found). HR ESI MS: calc. for C20H23O5NI [MþH]þ: m/z
484.0615; found: m/z 484.0586 (error 6.0 ppm).
102.8e104.3 ꢂC. 1H NMR (400 MHz, CDCl3)
d
8.68 (d, J ¼ 6 Hz, 2H),
4-(p’-Iodobenzyloxy)pyridine-2,6-dicarboxylic acid (36).
General procedure 1 was used with diisopropyl 4-(p’-iodobenzy-
loxy)pyridine-2,6-dicarboxylate (35, 0.75 g,1.6 mmol), THF (50 mL),
and 10% wt. aq. KOH (50 mL) to produce 0.61 g (98%) of white solid,
7.82 (s, 2H), 7.38 (d, J ¼ 6 Hz, 2H), 5.30 (m, 2H), 5.25 (s, 2H), 1.43 (d,
J ¼ 6.3 Hz, 11H). 13C NMR (126 MHz, CDCl3)
d 165.96, 163.98, 150.88,
150.36, 143.85, 121.51, 114.17, 70.31, 68.66, 21.81 (10 peaks expected
and 10 peaks found). HR ESI MS: calc. for C19H23N2O5 [MþH]þ: m/z
359.1601; found: m/z 359.1616 (error 4.2 ppm).
mp 187.3e189.8 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d 7.79 (m, 4H),
7.30 (d, J ¼ 8 Hz, 2H), 5.34 (s, 2H). 13C NMR (126 MHz, DMSO-d6)
4-(4′-Pyridylmethoxy)pyridine-2,6-dicarboxylic acid (40).
General procedure 1 was used with diisopropyl 4-(pyridin-40-
ylmethoxy)pyridine-2,6-dicarboxylate (39, 0.39 g, 1.1 mmol), 10%
wt. aq. KOH (20 mL) and THF (20 mL) to produce a white solid,
56.6 mg (19%), mp 205.1e207.3 ꢂC (dec.). 1H NMR (500 MHz, DMSO-
d
166.27, 165.23, 149.78, 137.34, 135.41, 129.96, 113.91, 94.44, 69.40
(9 peaks expected and 9 peaks found). HR ESI MS: calc. for
C
14H11O5NI [MþH]þ: m/z 399.9676; found: m/z 399.9709 (error
8.3 ppm).
p-[p’-Bromobenzyloxy]benzyl bromide. To a flask containing
d6)
NMR (126 MHz, DMSO-d6)
d C
8.93 (br s, 2H), 8.09 (br s, 2H), 7.90 (br s, 2H), 5.74 (br s, 2H). 13
DCM (200 mL) were added p-(p’-bromobenzyloxy)benzyl alcohol
(6.88 g, 23.5 mmol) and PBr3 (1.4 mL, 15 mmol) with magnetic
stirring under nitrogen. The solution was held at reflux for 39 h,
after which it was poured into water, followed by washing the
organic phase with water (x2), saturated aq. NaCl (x2) and drying
over sodium sulfate. Filtration and removal of the solvent provided
the product as a light brown solid, 8.21 g (98%), mp 76.4e78.8 ꢂC. 1H
d 165.68, 165.19, 149.99, 143.07, 142.77,
123.85, 113.99, 67.77 (8 signals expected and 8 signals found). HR
ESI MS: calc. for C13H11N2O5 [MþH]þ: m/z 275.0662; found: m/z
275.0674 (error 4.4 ppm).
Diisopropyl
4-(p’-formylphenoxyethoxy)pyridine-2,6-
dicarboxylate (41). To a round bottom flask containing acetone
(125 mL) were added p-(20-bromoethoxy)benzaldehyde (4.77 g,
18.5 mmol), diisopropyl chelidamate (21c, 4.14 g, 15.5 mmol), and
K2CO3 (3.82 g, 27.6 mmol) with magnetic stirring. The mixture was
held at reflux under nitrogen for 31 h, filtered through Celite p545®
and evaporated to provide a material which was purified by flash
NMR (400 MHz, CDCl3)
7.31 (d, J ¼ 8 Hz, 2H), 6.91 (d, J ¼ 8 Hz, 2H), 5.01 (s, 2H), 4.49 (s, 2H).
13C NMR (101 MHz, CDCl3)
158.77, 135.96, 131.96, 130.74, 130.69,
129.27, 122.20, 115.27, 69.51, 34.00 (10 peaks expected and 10 large
d
7.51 (d, J ¼ 8 Hz, 2H), 7.34 (d, J ¼ 8 Hz, 2H),
d
9

H.W. Gibson, T.L. Price Jr., A.M.-P. Pederson et al.
Tetrahedron 94 (2021) 132333
column chromatography (silica gel, eluting with DCM/EA). The
product was found in the third fraction as a yellow tinted solid:
DCM (20 mL) and 4-benzyloxy-2,6-pyridinedicarboxylic acid
dichloride (52, 0.18 g, 0.57 mmol) in DCM (20 mL) were added
separately by syringe pump at 0.75 mL/h to a mixture of pyridine
(0.1 mL, 1 mmol, dried) and dichloromethane (1.5 L, distilled from
P2O5). The mixture was stirred for an additional 5 d after addition.
The solvent was evaporated, yielding about 2 g of crude yellow oil.
The crude product was dissolved in chloroform and washed with
2 M H2SO4 and then H2O. The organic phase was dried with Na2SO4,
filtered, and the solvent was evaporated. The product was then
subjected to alumina chromatography (elution with CHCl3) to
afford a colorless solid (0.20 g, 42%), mp 150.8e154.0 ꢂC. 1H NMR
3.10 g (48%), mp 111.8e112.9 ꢂC. 1H NMR (500 MHz, CDCl3)
d 9.91 (s,
1H), 7.87 (d, J ¼ 9 Hz, 2H), 7.81 (s, 2H), 7.06 (d, J ¼ 9 Hz, 2H), 5.30
(hept, J ¼ 6 Hz, 2H), 4.55 (dd, J ¼ 6, 3 Hz, 2H), 4.48 (dd, J ¼ 6, 3 Hz,
2H), 1.43 (d, J ¼ 6 Hz, 12H). 13C NMR (126 MHz, CDCl3)
d 190.69,
166.31, 164.04, 163.16, 150.74, 132.03, 130.54, 114.83, 114.07, 70.23,
66.88, 66.25, 21.80 (13 peaks expected and 13 peaks found). HR ESI
MS: calc. for C22H25NO7 [MþH]þ: m/z 416.1704; found: m/z
416.1700 (error ꢀ1 ppm).
Diisopropyl 4-[(p’-formylphenoxyethoxy)-p”-benzyloxy]pyr-
idine-2,6-dicarboxylate (42). To a flask containing 60 mL of
acetone was added p-[(p’-chloromethyl)benzyloxy]benzaldehyde
(0.88 g, 3.4 mmol), diisopropyl chelidamate (21c) and K2CO3
(0.90 g, 6.5 mmol) with magnetic stirring under nitrogen. The re-
action mixture was held at reflux for 31 h. After cooling to room
temperature the mixture was passed through Celite® p545 and
solvent was removed by rotary evaporation. The desired product
was obtained by triturating the crude material with hexanes: 0.94 g
(59%) of colorless solid, mp 124.4e127.4 ꢂC$1H NMR (500 MHz,
(CDCl3, 400 MHz) d: 7.91 (s, 2H), 7.47e7.35 (m, 5H), 6.94 (m, 4H),
6.77 (m, 2H), 5.31 (s, 4H), 5.25 (s, 2H), 4.16 (m, 4H), 4.00 (m, 4H),
3.93 (m, 4H), 3.83 (m, 4H), 3.75 (m, 4H), 3.70 (m, 8H), 3.65 (m, 4H).
LR FAB MS (NBA): m/z 833.5, 10% [M]þ; 834.5, 100% [MþH]þ; 835.5,
50% [MþHþ1]þ; 836.5, 13% [MþHþ2]þ; 837.5, 3% [MþHþ3]þ; HR
FAB MS (NBA/PEG): m/z 834.3356 [MþH]þ, calcd. for C44H52NO15
:
834.3337, error 2.2 ppm.
Dibnzo-30-crown-10-based formyl functionalized cryptand
51. Diacid 23 (0.21 g, 0.58 mmol) was stirred in refluxing SOCl2
(25 mL) under N2 for 12 h. The mixture was cooled and solvent was
evaporated, yielding a brown oily material, which was used in the
next reaction without further purification. The diacid chloride
(assumed to be 0.58 mmol) was dissolved in toluene (40 mL) and
cis-DB30C10 diol (7, 0.344 g, 0.58 mmol) was dissolved in chloro-
form (40 mL). The reactants were separately added at 0.2 mL/h via
syringe pump to a solution of 1 mL pyridine in 2.0 L of DCM
(distilled from P2O5). The mixture was stirred for 5 d after the
addition of the reactants. The solvent was evaporated, producing a
yellow oily solid. This material was dissolved in CHCl3 and washed
with 5% HCl (x2), water and NaCl (sat.). The organic phase was dried
with Na2SO4 and the solid was filtered and the solvent was evap-
orated to a yellow solid, which was purified using alumina chro-
matography (2.5% CH3OH in EA): 0.12 g (23% yield), which
CDCl3)
d
9.90 (s, 1H), 7.85 (d, J ¼ 8.8 Hz, 2H), 7.82 (s, 2H), 7.49 (s, 4H),
7.08 (d, J ¼ 8.8 Hz, 2H), 5.29 (hept, J ¼ 6.3 Hz, 2H), 5.23 (s, 2H), 5.18
(s, 2H), 1.42 (d, J ¼ 6.3 Hz, 12H). 13C NMR (126 MHz, CDCl3)
d 190.74,
166.38, 164.10, 163.54, 150.68, 136.62, 135.00, 132.02, 130.28, 128.15,
127.89, 115.14, 114.34, 70.32, 70.22, 69.81, 21.81 (17 peaks expected
and 17 peaks found). HR ESI MS: m/z 491.1956 [M]þ; calc. for
C
28H29NO7 491.1944, error ꢀ2.4 ppm.
Diisopropyl 4-(p’-(200-tosyloxyethoxy)phenoxyethoxy)pyri-
dine-2,6-dicarboxylate (45). To
a flask containing acetone
(300 mL) were added p-bis(20-tosyloxyethoxy)benzene (3.33 g,
6.57 mmol), diisopropyl chelidamate (21c, 3.59 g, 13.4 mmol) and
K2CO3 (3.18 g, 23.0 mmol) with magnetic stirring under a stream of
nitrogen. The reaction mixture was held at reflux for 24 h, cooled to
room temperature, filtered through Celite p545® and the solvent
was removed by rotary evaporation. The crude material was dis-
solved in DCM and washed with aq. Na2CO3 (x2), saturated aq. NaCl
(x3) and dried over sodium sulfate. After filtration and removal of
solvent, the material was purified by silica flash column chroma-
tography, eluting with DCM to acetonitrile, 1.47 g (37%), a white
solid 48:50 ¼ 4:1, mp 102.4e109.1 ꢂC. 1H NMR (500 MHz, CDCl3,
decomposed prior to obtaining a mp. 1H NMR (CDCl3, 400 MHz)
d:
9.90 (s, 1H), 7.85 (d, J ¼ 8Hz, 2H), 7.83 (s, 2H), 7.01 (d, J ¼ 8 Hz, 2H),
6.95 (m, 4H), 6.77 (m, 2H), 5.31 (s, 4H), 4.25 (m, 2H), 4.17 (m, 6H),
4.01 (m, 4H), 3.94 (m, 4H), 3.82 (m, 4H), 3.75 (m, 5H), 3.71 (m, 9H),
3.66 (m, 5H), 2.07 (m, 4H). LR FAB MS (NBA): m/z 392.1, 50%
[MeCH2OC6H4CHO]2þ; 393, 11% [MeCH2OC6H4CHO þ 1]2þ; 418,
25% [MeC6H5CHO þ Na]2þ; 419, 5% [MeC6H5CHOþNaþ1]2þ; 461.0,
100% [M]2þ; 462, 27% [Mþ1]2þ; 473, 45% [MþNa]2þ; 474, 13%
[MþNa]2þ; 920.7, 7% [MþH]þ; 921.8, 28% [MþHþ1]þ; 922.8, 14%
[MþHþ2]þ; 923.8, 4% [MþHþ3]þ. HR FAB MS (PEG): m/z 920.3666
[MþH]þ, calc'd for C48H58NO17: 920.3705, error ꢀ4.2 ppm.
major signals only)
d
7.84 (d, J ¼ 8 Hz, 2H), 7.82 (s, 2H), 7.37 (d,
J ¼ 8 Hz, 2H), 6.86 (d, J ¼ 9 Hz, 2H), 6.77 (d, J ¼ 9 Hz, 2H), 5.32 (hept,
J ¼ 6 Hz, 2H), 4.53e4.46 (m, 2H), 4.39e4.35 (m, 2H), 4.35e4.32 (m,
2H), 4.16e4.10 (m, 2H), 2.48 (s, 3H), 1.45 (d, J ¼ 6 Hz, 12H). 13C NMR
(126 MHz, CDCl3, major signals only)
d 166.50, 164.11, 152.97,
152.76, 150.68, 144.92, 132.96, 129.85, 128.03, 115.84, 115.69, 114.14,
70.17, 68.17, 67.29, 66.70, 66.25, 21.81, 21.66 (19 peaks expected and
19 peaks found). HR MS: calc. for C30H36NO10S [MþH]þ: m/z
602.2054; found: m/z 602.2064 (error 1.7 ppm).
Dibenzo-30-crown-10-based Diamide Cryptand 54. 4-(Ben-
zyloxy)pyridine-2,6-diamine (52, 0.17 g, 0.78 mmol) was dissolved
in 700 mL of dry DCM (distilled from CaH2). To this, PyTFSI (1.4 g,
3.9 mmol), and pyridine (1.2 mL, 15.6 mmol) were added and stir-
red for 30 min. Then, the cis-diacid chloride of dibenzo-30-crown-
10 (53, 0.52 g, 0.78 mmol) was added and the mixture was stirred
for 48 h at room temperature. The solvent was removed by rotary
evaporation and the crude material was subjected to column
chromatography on basic alumina eluting with EA/hexane (1:1
v:v), affording a colorless solid, 0.133 g (21%). 1H NMR (400 MHz,
4-[p’-(200-Tosyloxyethoxy)phenoxyethoxy]pyridine-2,6-
dicarboxylic acid (46). General procedure 1 was used with diiso-
propyl
4-[p’-(200-tosyloxyethoxy)phenoxyethoxy]pyridine-2,6-
dicarboxylate (45, 0.2570 mg, 0.4271 mmol), 10% wt. aq. KOH
(20 mL) and THF (40 mL) to produce 0.2051 g (93%) of colorless
solid, mp 103.8e107.3 ꢂC. 1H NMR (500 MHz, DMSO-d6)
d 7.79 (d,
J ¼ 8 Hz, 2H), 7.76 (s, 2H), 7.47 (d, J ¼ 8 Hz, 2H), 6.87 (d, J ¼ 9 Hz, 2H),
6.77 (d, J ¼ 9 Hz, 2H), 4.58e4.53 (m, 2H), 4.31e4.26 (m, 4H),
4.10e4.07 (m, 2H), 2.41 (s, 3H). 13C NMR (126 MHz, DMSO-d6)
CDCl3)
d
: 7.69 (dd, J ¼ 2, 2 Hz, 2H), 7.56 (d, J ¼ 4 Hz, 2H), 7.44e7.33
(m, 8H), 6.85 (d, J ¼ 8 Hz, 2H), 5.32 (s, 2H), 4.18e4.16 (m, 8H),
3.90e3.87 (m, 8H), 3.78e3.75 (m, 8H), 3.69e3.66 (m, 8H). 13C NMR
d
166.60, 165.34, 152.55, 152.05, 149.82, 145.06, 132.27, 130.20,
(101 MHz, CDCl3) d 166.11, 153.02, 148.26, 136.21, 128.56, 128.15,
127.70, 115.59, 115.47, 113.76, 69.27, 67.67, 66.48, 65.85, 21.13 (17
peaks expected and 17 peaks found). HR ESI MS: calc. for
128.12, 124.09, 122.81, 114.74, 112.24, 70.98, 70.92, 70.71, 70.68,
69.59, 69.45, 69.15, 68.88, 66.50 (23 peaks expected, 20 peaks
observed). HR ESI MS: m/z 822.3705, (MþNH4)þ; calculated for
C
24H24NO10
S
[M
þ
H]þ: m/z 518.1115; found: m/z 518.1077
(error ꢀ7.3 ppm).
C42H54N4O13: 822.3687, error 2.2 ppm.
Dibenzo-30-crown-10-based 4-benzyloxypyridyl cryptand
(50). cis-DB30C10 diol (7, 0.34 g, 0.57 mmol, dried in a pistol) in
10

H.W. Gibson, T.L. Price Jr., A.M.-P. Pederson et al.
Tetrahedron 94 (2021) 132333
[20] H.W. Gibson, H. Wang, C. Slebodnick, J. Merola, S. Kassel, A.L. Rheingold, J. Org.
Chem. 72 (2007) 3381.
Declaration of competing interest
[21] F. Huang, J.W. Jones, C. Slebodnick, H.W. Gibson, J. Am. Chem. Soc. 125 (2003)
14458.
There are no competing interests to declare.
[22] T.B. Gasa, J.M. Spruell, W.R. Dichtel, T.J. Sorensen, D. Philp, J.F. Stoddart,
P. Kuzmic, Chem. Eur J. 15 (2009) 106.
[23] H.W. Gibson, J.W. Jones, L.N. Zakharov, A.L. Rheingold, C. Slebodnick, Chem.
Eur J. 17 (2011) 3192.
Acknowledgements
[24] T.L. Price Jr., H.R. Wessels, C. Slebodnick, H.W. Gibson, J. Org. Chem. 82 (2017)
8117.
[25] H.W. Gibson, H. Wang, K. Bonrad, J.W. Jones, C. Slebodnick, B. Habenicht,
P. Lobue, Org. Biomol. Chem. 3 (2005) 2114.
The authors wish to thank the National Science Foundation
(USA) for generous support of these efforts through grants DMR-
0097126, DMR-0704076, CHE-1106899 and CHE-1507553.
[26] H.R. Wessels, H.W. Gibson, Tetrahedron 72 (2016) 396.
ꢁ
€
€
ꢁ
[27] G. Howath, C. Rusa, Z. Kontos, J. Gerencser, P. Huszthy, Synth. Commun. 29
(1999) 3719.
Appendix A. Supplementary data
[28] S. Gao, L. Shi, L. Chang, B. Wang, J. Fu, Synthesis 53 (2021) 861.
[29] B. Lamture, Z.H. Zhou, A.S. Kumar, T.G. Wensel, Inorg. Chem. 34 (1995) 864.
[30] T.A. Geissman, Org. React. 2 (1944) 94.
[31] T.L. Price Jr., C. Slebodnick, H.W. Gibson, Heteroat. Chem. 28 (2017), e21406.
[32] T.L. Price Jr., H.W. Gibson, J. Am. Chem. Soc. 140 (2018) 4455.
[33] W. Risse, R.H. Grubbs, Macromolecules 22 (1989) 1558.
[34] S. Hilf, A.F.M. Kilbinger, Nat. Chem. 1 (2009) 537.
[35] A.K. Pearce, J.C. Foster, R.K. O'Reilly, J. Polym. Sci., Part A: Polym. Chem. 57
(2019) 1621.
[36] I.S.S. Pinto, I.F.F. Neto, H.M.V.M. Soares, Environ. Sci. Pollut. Res. 21 (2014)
11893.
[37] D. Saha, T. Maity, S. Koner, Eur. J. Inorg. Chem. (2015) 1053.
[38] S. Pachisia, R. Gupta, Dalton Trans. 49 (2020) 14731.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132333.
References
[1] F. Huang, H.W. Gibson, Prog. Polym. Sci. 30 (2005) 982.
[2] L. Fang, M.A. Olson, D. Benıtez, E. Tkatchouk, W.A. Goddard III, J.F. Stoddart,
Chem. Soc. Rev. 39 (2010) 17.
[3] P.A. Gale, J.W. Steed (Eds.), Supramolecular Chemistry: from Molecules to
Nanomaterials, 6 Volumes, John Wiley & Sons Ltd., Chichester, UK, 2012.
[4] M. Arunachalam, H.W. Gibson, Prog. Polym. Sci. 39 (2014) 1043.
[5] Special issue: Chem. Rev. 115 (2015) 15.
ꢁ
ꢁ
ꢁ ꢁ
[39] J. Kupai, P. Huszthy, K. Szekely, T. Toth, L. Parkanyic, ARKIVOC Ix, 2011, p. 77.
[40] S.J. Bradberry, A.J. Savyasachi, R.D. Peacock, T. Gunnlaugsson, Faraday Discuss
185 (2015) 413.
[6] J.L. Atwood, G.W. Gokel, L.J. Barbour (Eds.), Comprehensive Supramolecular
Chemistry, 9 Volumes, Elsevier, Ltd., London, 2017.
[41] T.G. Ribelli, F. Lorandi, M. Fantin, K. Matyjaszewski, Macromol. Rapid Com-
mun. 40 (2019) 1800616.
[7] T. Takata, Bull. Chem. Soc. Jpn. 92 (2019) 409.
[8] S. Mena-Hernando, E.M. Perez, Chem. Soc. Rev. 48 (2019) 5016.
[9] A. Hashidzume, H. Yamaguchi, A. Harada, Eur. J. Org Chem. 21 (2019) 3344.
[10] C.B. Thompson, L.T.J. Korley, ACS Macro Lett. 9 (2020) 1198.
[11] D. Xia, P. Wang, X. Ji, N.M Khashab, J.L. Sessler, F. Huang, Chem. Rev. 120
(2020) 6070.
[12] H.W. Gibson, ch. 6, in: J.A. Semlyen (Ed.), Large Ring Molecules, J. Wiley and
Sons, New York, 1996, pp. 191e262.
[13] M. Asakawa, P.R. Ashton, R. Ballardini, V. Balzani, M. Belohradský,
M.T. Gandolfi, O. Kocian, L. Prodi, F.M. Raymo, J.F. Stoddart, M. Venturi, J. Am.
Chem. Soc. 119 (1997) 302.
[14] W.S. Bryant, J.W. Jones, P.E. Mason, I. Guzei, A.L. Rheingold, F.R. Fronczek,
D.S. Nagvekar, H.W. Gibson, Org. Lett. 1 (1999) 1001.
[15] F. Huang, K.A. Switek, L.N. Zakharov, F. Fronczek, C. Slebodnick, M. Lam,
J.A. Golen, W.S. Bryant, P. Mason, M. Ashraf-Khorassani, A.L. Rheingold,
H.W. Gibson, J. Org. Chem. 70 (2005) 3231.
[42] G. Audran, E.G. Bagryanskaya, S.R.A. Marque, P. Postnikov, Polymers 12 (2020)
1481.
ꢁ
[43] R. Chinchilla, C. Najera, Chem. Soc. Rev. 40 (2011) 5084.
[44] B.S. Kadu, Catal. Sci. Tech. 11 (2021) 1186.
[45] J. Recker, W.M. Müller, U. Müller, T. Kubota, Y. Okamoto, M. Nieger, F. Vogtle,
€
Chem. Eur J. 8 (2002) 4434.
[46] T. Braxmeier, M. Demarcus, T. Fessmann, S. McAteer, J.D. Kilburn, Chem. Eur J.
7 (2001) 1889.
[47] A.M.-P. Pederson, T.L. Price Jr., D.V. Schoonover, C. Slebodnick, H.W. Gibson,
Heteroat. Chem. 29 (2018), e21422.
[48] A. Picot, C. Feuvrie, C. Barsu, F. Malvolti, B. Le Guennic, H. Le Bozec, C. Andraud,
L. Toupet, O. Maury, Tetrahedron 64 (2008) 399.
ꢀ
[49] S. Vassiliou, M. Xeilari, A. Yiotakis, J. Grembecka, M. Pawełczak, P. Kafarski,
A. Mucha, Bioorg. Med. Chem. 15 (2007) 3187.
[50] W.W.H. Wong, D. Curiel, A.R. Cowley, P.D. Beer, Dalton Trans. (2005) 359.
[51] V. Biju, P.K. Sudeep, K.G. Thomas, M.V. George, S. Barazzouk, P.V. Kamat,
Langmuir 18 (2002) 1831.
[52] X. Pan, F. Yi, X. Zhang, S. Chen, Asian J. Chem. 24 (2012) 3809.
[53] L.-F. Pan, X.-B. Wang, S.-S. Xie, S.-Y. Li, L.-Y. Kong, Med. Chem. Commun. 5
(2014) 609.
[16] B.L. Allwood, H. Shahriari-Zavareh, J.F. Stoddart, D.J. Williams, J. Chem. Soc.,
Chem. Commun. (1987) 1058.
[17] C. He, Z. Shi, Q. Zhou, S. Li, N. Li, F. Huang, J. Org. Chem. 73 (2008) 5872.
[18] A.M.-P. Pederson, E. Ward, D.S. Schoonover, C. Slebodnick, H.W. Gibson, J. Org.
Chem. 73 (2008) 9094.
[19] A.M.-P. Pederson, T.L. Price Jr., C. Slebodnick, D.V. Schoonover, H.W. Gibson,
J. Org. Chem. 82 (2017) 8489.
[54] A.M. Sanseverino, M.C.S. de Mattos, J. Braz. Chem. Soc. 12 (2001) 1678.
11