Synthesis, crystal structure, and different local conformations of pyridine-imide oligomers

Article abstract of DOI:10.1016/j.tet.2011.09.006

In this article, we report a new approach toward synthesis of pyridine-imide oligomers (PIOs). Using this approach, both dimer and trimer were one-pot synthesized from acylation of monomeric monoamide with monomeric dichloride. The yield of trimer was dependent on the alkoxyl terminals: it was 30% for methoyl group, whereas it was 95% for 3-chloro-1-propoxyl terminal. Acylation of dimeric monoamide with monomeric dichloride produced trimer, tetramer, and pentamer in a yield of 34%, 33%, and 28%, respectively. The synthesis was proposed to be mediated through an exchange between pyridine-2-carboxamide and pyridine-2-carbonyl chloride, both forming intramolecular or intermolecular hydrogen-bonds between pyridine-nitrogen and pyridine-2-amide hydrogen atoms. Crystal structure from three trimers with different terminal groups was reported. Analysis on the crystal structures revealed that these three trimers had different local conformations. The different local conformations were originated from the structural tunability of the imide unit in either the coplanarity or bond parameters.

Full text of DOI:10.1016/j.tet.2011.09.006

Tetrahedron 67 (2011) 8458e8464
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis, crystal structure, and different local conformations of pyridineeimide
oligomers
,
,
,
a
b
c
Hengheng Zhu a b, Weiwei He a c, Chuanlang Zhan a , Xiao Li , Zisheng Guan , Fengqi Guo ,
*
,
Jiannian Yao a
*
a Beijing National Laboratory of Molecular Science, Laboratory of Photochemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China
b College of Materials Science and Engineering, Nanjing University of Technology, Nanjing 210009, Jiangsu Province, PR China
c Department of Chemistry, Zhengzhou University, Zhengzhou 450001, Henan Province, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 July 2011
Received in revised form 29 August 2011
Accepted 6 September 2011
Available online 8 September 2011
In this article, we report a new approach toward synthesis of pyridineeimide oligomers (PIOs). Using this
approach, both dimer and trimer were one-pot synthesized from acylation of monomeric monoamide
with monomeric dichloride. The yield of trimer was dependent on the alkoxyl terminals: it was 30% for
methoyl group, whereas it was 95% for 3-chloro-1-propoxyl terminal. Acylation of dimeric monoamide
with monomeric dichloride produced trimer, tetramer, and pentamer in a yield of 34%, 33%, and 28%,
respectively. The synthesis was proposed to be mediated through an exchange between pyridine-2-
carboxamide and pyridine-2-carbonyl chloride, both forming intramolecular or intermolecular
hydrogen-bonds between pyridineenitrogen and pyridine-2-amide hydrogen atoms. Crystal structure
from three trimers with different terminal groups was reported. Analysis on the crystal structures re-
vealed that these three trimers had different local conformations. The different local conformations were
originated from the structural tunability of the imide unit in either the coplanarity or bond parameters.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
hydrogen-bonding direction and rigidity of the molecular strand, as
compared to the aliphatic analogues.
A biomacromolecule, such as nucleic acid and peptide is able to
fold into secondary structures through noncovalent forces, for ex-
amples, hydrogen-bonding, hydrophilic, and hydrophobic in-
teractions. Inspired by this, a number of synthetic foldamers have
been developed in the past decades.1 These foldamers have opened
a way to mimic the secondary and higher structures and even
functions of natural biomacromolecules.2 They are constituted
chemically by diverse building blocks varying from aliphatics to
By selecting the imide as a hydrogen-bonding function, we have
developed pyridineeimide oligomers (PIOs), a type of AOAs. Crystal
structure revealed that the imideehydrogen atom was able to form
highly stable intra-strand hydrogen-bonds with the pyridine nitro-
gen atom, which compressed the molecular strand into a highly
compact helix with every three pyridine and two imide units con-
stituting a helical turn.19 A way to synthesize the pyridineeimide
function is through acylation of pyridine-2-carboxamide with pyri-
dine-2-carbonyl chloride (Scheme 1). However, synthesis of PIOs is
relatively difficult because the yield is relatively low, for example, the
yield to trimer and tetramer is only about 15% and 10%, respective-
ly.19a Thus, it is difficult for us to get longer oligomers than tetramer
throughsuch step-by-stepsynthesis. Herein, wepresentanapproach
toward synthesis of trimeric, tetrameric, and pentameric PIOs. This
approach is based on a hydrogen-bonding enhanced exchange be-
tween pyridine-2-carboxamide and pyridine-2-carbonyl chloride.
aromatics, for instances, aliphatic analogues of the a a-
-peptides,3,4
helix face mimetics by projecting the side chains of oligo-aromatics
into an analogous fashion to the natural peptides,5 aromatic oli-
goamides (AOAs),1bed and others.6e9 Among which AOAs are con-
structed from aromatics, such as pyridine-,10 benzene-,11e13
quinoline-,14 and phenanthroline-derivatives15,16 and hydrogen-
bonding functions, such as amide,10e16urea,17 and hydrazine.18
The coherent intra-strand or inter-strand hydrogen-bonds formed
between the aromatic units and hydrogen-bonding functions direct
formation of either canonical helical conformations or linear
hydrogen-bonding assembly.1 One of the outstanding features of
AOAs is the strong structural predictability due to the predictable
* Corresponding authors. Tel./fax: þ86 10 82617312; e-mail addresses: clzhan@
Scheme 1. Formation of a typical pyridineeimide function.
iccas.ac.cn (C. Zhan), jnyao@iccas.ac.cn (J. Yao).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.006

H. Zhu et al. / Tetrahedron 67 (2011) 8458e8464
8459
2. Results and discussion
and 2 was 1:0.7. Adjustment of the molar ratio into 1:2.5 produced
both dimer 6c and trimer 7c in a yield of 42% and 50%, respectively.
When 3-chloro-1-propoxyl was introduced, reaction of 5d and 2
in a molar ratio of 1:0.7 produced trimer 7d in a yield up to 95%.
Dimer 6d was isolated only in a yield of 5%. No 5d was detected.
Formation of dimer 6a, 6b, 6c, and 6d suggests an exchange
appears between pyridine-2-carboxamide and pyridine-2-carbonyl
chloride (Scheme 4a). To address this, we preformed a reaction
between 5c and 8a (Scheme 4b). 4 h later, the reaction yielded
a dimeric product formed from condensation of 5c and 8a. TLC
revealed trace of 5a was detected, in addition to 8a. 1H NMR spectra
further confirmed formation of 5a. This strongly supports the am-
ide/chloride exchange. The one-pot yield toward the dimer and
trimer likely relates with solubility of the reactants. The solubility
of 2-alkoxycarbonyl-pyridine-6-carbonyl chloride in toluene is in
the sequence of 5a<5b<5c<5d.
2.1. One-pot synthesis of dimeric and trimeric PIOs
Scheme 2 shows the synthetic procedure of the monomeric
monoamide. Pyridine-2,6-dicarboxylic acid (1) was first converted
into pyridine-2,6-dicarbonyl chloride (2), which was then reacted
with 1.2 equivalence of alcohol to yield monomeric monoacid (3)
and monomer (4). Reaction of 3 and SOCl2 produced monomeric
monochloride that was then converted into monomeric mono-
amide (5) by bubbling ammonia gas into the dichloromethane
solution of the monochloride.
(a)
(b)
Scheme 2. Synthesis of monomeric monoamide (5). Reactants and conditions: (i)
SOCl2/reflux; (ii) alcohol (1.2 equiv), DIEA (1.2 equiv), THF/reflux, and then H2O, yield:
50e70% for 3 and 30e40% for 4; (iii) SOCl2/reflux, and (iv) NH3, CH2Cl2/rt, yield:
70e90% for 5.
Scheme 4. The exchange between pyridine-2-carboxamide and pyridine-2-carbonyl
chloride.
Trimeric
PIO
was
synthesized
from
acylation
of
2-alkoxycarbonyl-pyridine-6-carboxamide (5) and pyridine-2,6-
dicarbonyl chloride (2) in a molar ratio of 1:0.7 (5:2) and this re-
action yielded about 10e20% of trimer and more than 80% of 5 was
recovered. Occasionally, the molar ratio of 5b and 2 was adjusted to
1:2.5 and it was surprising that both dimer (6b) and trimer (7b)
were isolated in a yield of 54% and 37%, respectively, whereas no
unreacted 5b was detected (Scheme 3). The total yield of 6b and 7b
was 91%, meaning that 5b was almost completely converted into
products. A change in the molar ratio of 5b and 2, for example, into
1:2.0 and 1:1.5 lowered the yield of dimer (30e45%) and trimer
(15e30%), accompanying 20e35% of 5b unreacted.
2.2. One-pot synthesis of trimeric, tetrameric, and
pentameric PIOs
To further address the amide/chloride exchange, we performed
acylation reaction of dimeric monoamide and 2. Dimeric mono-
amide was synthesized by following the procedure in Scheme 5.
Compound 3d was converted into chloride and then reacted with 5d
to yielded dimer 6d in a yield of 68%. Partial hydrolysis of 6d in
a mixture of dioxane and water (10:1 in v/v) by dropwise adding 1 M
aqueous solution of NaOH inside produced dimeric monoacid (10) in
a yield of 55%. Compound 10 was then converted into dimeric
monochloride and then dimeric monomamide (11) in a yield of 90%.
H
N
O
O
N
N
R
R
5
O
O
O
O
6
(i)
H
N
H
N
+
2
O
O
N
N
N
R
R
O
O
O
O
O
O
7
5c: R=-(CH2)2CH3
6c: R=-(CH2)2CH3
5d: R=-(CH2)3Cl
6d: R=-(CH2)3Cl
7d: R=-(CH2)3Cl
5a: R=-CH3
6a: R=-CH3
7a: R=-CH3
5b: R=-CH2CH3
6b: R=-CH2CH3
7b: R=-CH2CH3
7c: R=-(CH2)2CH3
Scheme 3. Synthesis of dimer (6) and trimer (7) by acylation of monomeric mo-
moamide with pyridine-2,6-dicarbonyl chlorides. Reactants and conditions: (i) tolu-
ene/reflux, overnight.
Replacement of ethoxyl group in 5bwith methoxyl or n-propoxyl
yielded similar results (Scheme 3). When the molar ratio of 5a and 2
was controlled as 1:0.7, trimer 7a was isolated in a yield of 15%.
However, if the molar ratio was adjusted as 1:2.5, both dimer 6a and
trimer 7a were got in a yield of 60% and 30%, respectively. Similarly,
trimer 7c was isolated in a yield of 20% when the molar ratio of 5c
Scheme 5. Synthesis of dimeric monoamide (11). Reactants and conditions: (i) SOCl2/
reflux; (ii) toluene/reflux, overnight; (iii), dioxane/H2O (10:1), NaOH (1 M), yield:
60e70%; (iv) SOCl2/reflux; (v) NH3/CH2Cl2, yield: 80e95%.

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H. Zhu et al. / Tetrahedron 67 (2011) 8458e8464
Reaction of dimeric monoamide (11) and 2 in an equivalence of
2.4. NMR spectra of the PIOs
1:0.7 yielded trimer (7d), and tetramer (12), pentamer (13) in
a yield of 34%, 33%, and 28%, respectively (Scheme 6), suggesting
nearly 100% conversion of the starting material of 11. Pentamer (13)
is the expected product. It should be noted that pentameric PIO was
first achieved by following this approach. Yield of tetramer (12)
reveals an amide/chloride exchange between 11 and 2. Formation
of trimer 7b is likely due to decomposition of 11.
Fig. 1 shows 1H NMR spectra of PIOs 4d, 6d, 7d, 12, and 13. As
compared to the monomer (4d), the pyridine hydrogens of the
dimer (6d) is downfield shifted, due to the formation of intra-
molecular hydrogen-bonding between the imide hydrogen and the
pyridine nitrogen atoms. Similar to our previous observations,19a
formation of helical conformations with the oligomeric length go-
ing from dimeric (6d) up to trimeric (7d) led to a distinct upfield
shift of the 3-Cl-1-propyl hydrogens because of overlapping of
propyl hydrogens with the pyridine ring. Formation of helical
structure is further confirmed by the distinctly upfield shift of the
imide hydrogens: the imide hydrogens are downfield shifted firstly
from 12.88 ppm for the dimer (6d) to 13.02 ppm for the trimer (7d)
and then upfield shifted dramatically to 12.81 and 12.53 ppm for
the tetramer (12) and to 12.38 and 12.30 ppm for the pentamer (13)
because of the shielding effects from the pyridine units upon for-
mation of helical structure.
Scheme 6. One-pot synthesis of trimer (7d), tetramer (12), and pentamer (13) by
acylation of dimer monoamide (11) and pyridine-2,6-dicarbonyl chloride (2). Reactants
and conditions: (i), toluene/reflux, overnight.
2.3. Possible models of the amide and chloride exchange
On the basis of H-bonding possibility formed between ami-
deehydrogen and pyridineenitrogen atoms,19 we proposed that
the amide/chloride exchange in toluene be mediated by intra-
molecular and intermolecular H-bonding (Scheme 7a). Pyridine-2-
carboxamide may be represented as resonance hybrids of three
structures (Scheme 7b).20 The intramolecular H-bonding stabilizes
the zwitterionic resonance VI, whereas the intermolecular
H-bonding formed between pyridine-2-carboxamide hydrogen
atom and 2-chloro-carbonyl-pyridine nitrogen atom brings two
molecules close to each other (II). Thus, the intramolecular and
intermolecular H-bonding both favor electrophilic substitution that
appears between VI and pyridine-2-carbonyl chloride to form car-
boxylate III. Rearrangement of carboxylate III yields pyridineeimide
function (IV). Obviously, equilibrium between IV and I is reversible
and this yields the amide/chloride exchange and decomposition of
the dimeric monoamide 11.
Fig. 1. 1H NMR spectra of the monomer (4d), dimer (6d), trimer (7d), tetramer (12),
and pentamer (13) in CDCl3 with a typical concentration of 5 mg/mL.
2.5. Crystal structure and different local conformations of the
trimeric PIOs
Helical structure was further supported by the crystal structure.
Fig. 2 shows the crystal structure of trimers 7a,22 7b,19b 7c,23 and
7d.24 All these four trimers form a similar helical structure with
every two imide and three pyridine units forming a helical turn.
However, the local conformations are different to each other, which
is due to the structural tunability of the imide unit.19a Bond
parameters and coplanarity of the imide unit are not only different
to each other for the two imide units located in the two arms of 7a,
7b, 7c, or 7d but also different to each other for the imide units in
the trimers of 7a, 7b, 7c, and 7d. As a result, the distance between
(a)
ꢀ
the two armed imideehydrogens is 2.777 A for 7a, whereas it is
ꢀ
2.788, 2.851, and 2.910 A, respectively, for 7b, 7c, and 7d. The helical
ꢀ
pitch measured between the terminal pyridine rings is 3.660 A for
(b)
7a, which is larger than that value for the other three trimers (all
ꢀ
close to 3.40 A).
Scheme 7. Possible models of the exchange between pyridine-2-carboxamide and
pyridine-2-carbonyl chloride.
Intramolecular and intermolecular H-bonding has been reported
to promote some reactions, for examples, leading to a high degree of
stereocontrol in the nucleophilic addition to quinolines,21a Michael
addition of methylene compounds to
and asymmetric addition to
a
,
b
-unsaturated imides,21b
-amino aldehydes,21c an efficient
a
macrocyclization of preorganized peptidomimetics21d and peptid-
es,21e stereoselectivity in synthesis of imidazolidin-4-one,21f and
structural selectivity in synthesis of 4-iso-butoy-10-hydroxy-1,7-
phenanthroline-2,8-dicarboxylic acid dimethyl ester.21g
Fig. 2. Solid state structures of trimers 7a, 7b, 7c, and 7d. The green numbers repre-
sent distances between the imide hydrogen atoms (top) and helical pitch between two
ꢀ
terminal pyridine rings (bottom). All values are in A. The pink lines represent intra-
molecular H-bonding between the imide hydrogen and pyridine nitrogen atoms.

H. Zhu et al. / Tetrahedron 67 (2011) 8458e8464
8461
Different local conformations were even observed from the
SOCl2 was then removed under vacuum. To the white solid of 2,
50 mL of THF was added. After the solid dissolved, alkyl alcohol
(10.5 mmol) and DIEA (10.5 mmol) were added using a syringe. The
resulted solution was allowed to reflux for 4 h. After removal of the
solvent the residue was applied to chromatography to afford the
desired products 3 and 4.
P- and M-helices for the trimer 7c, in which the two armed imide
ꢀ
units are separated by 2.851 and 2.919 A, respectively, whereas the
ꢀ
helical pitch is 3.323 and 3.358 A, respectively (Fig. 3).
4.2.1. 2-Methoxycarbonyl-pyridine-6-carboxylic acid (3a) and di-
methyl pyridine-2,6-dicarboxylate (4a). After removal of the sol-
vent, the residue was applied to chromatography with CH2Cl2/
acetonitrile (20:1) and CH2Cl2/ethyl acetate (20:1) as eluents for 3a
and 4a, respectively. Compound 3a was isolated as a white powder
(1.06 g, 5.84 mmol, yield¼65%) and 4a as a white solid (0.53 g,
2.69 mmol, yield¼30%). For 3a: 1H NMR (400 MHz, CDCl3) ppm:
8.43 (d, J¼7.60 Hz, 1H), 8.37 (d, J¼7.60 Hz, 1H), 8.13 (t, J¼7.60,
7.60 Hz, 1H), 4.04 (s, 3H). 13C NMR (100 MHz, CDCl3) ppm: 164.4,
147.9, 146.9, 139.8, 139.6, 128.7, 127.3, 51.5. TOF MS: m/z¼182.1
[MþH]þ, 204.1 [MþNa]þ. For 4a: 1H NMR (400 MHz, CDCl3) ppm:
8.30 (d, J¼7.60 Hz, 2H), 8.03 (t, J¼8.00, 8.00 Hz, 1H), 4.04 (s, 6H). 13C
Fig. 3. Different local conformations between the P- (colored in red) and M-helices
(colored in blue) of trimer 7c. The green numbers represent distances between the
imide hydrogen atoms (left) and helical pitch between two terminal pyridine rings
(right). All values are in A. The pink lines represent intramolecular H-bonding between
the imide hydrogen and pyridine nitrogen atoms.
ꢀ
3. Conclusions
NMR (100 MHz, CDCl3)
d ppm: 164.5, 148.7, 138.2, 127.8, 51.6. TOF
MS: m/z¼196.1 [MþH]þ.
We have developed an approach to one-pot synthesize PIOs on
the basis of an exchange between pyridine-2-carboxamide and pyr-
idine-2-carbonyl chloride. The trimeric PIO is in a yield of 30e90%
while dimeric PIO in a yield of 5e60%, depending on the length of
alkoyl tail. Acylation reaction of dimeric monoamide and pyridine-
2,6-dicarbonyl chloride yielded trimeric, tetrameric, and pentameric
PIOsin ayieldof34%, 33%, and28%, respectively. Oneof thefeatures is
that the amide reactant is nearlyconverted into products, the PIOs, in
100%. Crystal structure of the trimers with different terminal groups
reveals variabilityof thelocalconformationsof thetrimers, duetothe
structural tunability of the imide units.
4.2.2. 2-Ethoxycarbonyl-pyridine-6-carboxylic acid (3b) and diethyl
pyridine-2,6-dicarboxylate (4b). After removal of the solvent, the
residue was applied to chromatography with CH2Cl2/acetonitrile
(20:1) and CH2Cl2/ethyl acetate (20:1) as eluents for 3b and 4b,
respectively. Compound 3b was isolated as a white powder (1.26 g,
6.46 mmol, yield¼72%) and 4b as a white solid (0.47 g, 2.06 mmol,
yield¼23%). For 3b: 1H NMR (400 MHz, CDCl3) ppm: 8.41 (d,
J¼7.74 Hz, 1H), 8.37 (d, J¼7.80 Hz, 1H), 8.13 (t, J¼7.77, 7.77 Hz, 1H),
4.60 (q, J¼7.13, 7.13, 7.13 Hz, 2H), 1.46 (t, J¼7.13, 7.13 Hz, 3H). 13C
NMR (100 MHz, CDCl3) ppm: 164.5, 147.7, 146.8, 139.9, 139.7, 128.8,
127.2, 62.4, 14.5. TOF MS: m/z¼196.1 [MþH]þ, 218.1 [MþNa]þ. For
4b: 1H NMR (400 MHz, CDCl3) ppm 8.29 (d, J¼7.76 Hz, 2H), 8.02 (t,
J¼8.00, 8.00 Hz, 1H), 4.59 (t, J¼6.12, 6.12 Hz, 2H), 1.46 (t, J¼7.13,
4. Experimental part
4.1. Apparatus and materials
7.13 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d ppm: 164.6, 148.6, 138.2,
127.8, 62.3, 14.2. TOF MS: m/z¼224.1 [MþH]þ.
Starting materials are all commercially available reagents and
solvents used as received except for statements. Tetrahydrofuran
(THF) was distilled on sodium. All solvents were purified using
standard procedures. Reactions were monitored by thin-layer
chromatography (TLC) on pre-coated silica gel plates (Yantai Shi
Huagxue Gongye Yanjiusuo) and visualized using UV irradiation
(254 nm). Flash chromatography was performed on silica gel H60
(Giandao Haiyang Huagongchang).
Crystals suitable for the X-ray crystal diffraction studies were
obtained by a ‘vapor-diffusion’ method: ethyl ether, a poor solvent,
was allowed to diffuse into a solution of the N,N-dimethyl formamide
(DMF) solution of PIOs with a typical concentration of 40e50 mM.
1H and 13C-NMR spectra were recorded on a Bruker AVANCE 400
or AVANCE 600 spectrometer and referenced to solvent signals.
Chemical shifts were referenced to adamantane signals. ESI mass
spectrometric were obtained on LCeMS 2010 and BRUKER Apex IV
FTMS and MALDI-TOF mass spectrometric measurements were
performed on Bruker Biflex Ⅲ MALDI-TOF spectrometer. Crystal
4.2.3. 2-(n-Propoxycarbonyl)-pyridine-6-carboxylic acid (3c) and 2-
(n-propyl)-pyridine-2,6-dicarboxylate (4c). After removal of the
solvent, the residue was applied to chromatography with CH2Cl2/
acetonitrile (20:1) and CH2Cl2/ethyl acetate (20:1) as eluents for 3c
and 4c, respectively. Compound 3c was isolated as a white powder
(1.26 g, 6.02 mmol, yield¼67%) and 4c as a white solid (0.72 g,
2.87 mmol, yield¼32%). For 3c: 1H NMR (400 MHz, CDCl3) ppm:
8.41 (d, J¼7.74 Hz, 1H), 8.37 (d, J¼7.80 Hz, 1H), 8.13 (t, J¼7.77,
7.77 Hz, 1H), 4.47 (t, J¼6.40, 6.40 Hz, 2H), 1.86 (q, J¼6.80, 6.80,
6.80 Hz, 2H), 1.05 (t, J¼7.20, 7.20 Hz, 3H). 13C NMR (100 MHz, CDCl3)
ppm: 163.8, 146.7, 146.8, 139.8, 139.7, 128.9, 127.2, 68.9, 21.9, 10.5.
TOF MS: m/z¼210.1 [MþH]þ, 232.1 [MþNa]þ. For 4c: 1H NMR
(400 MHz, CDCl3) ppm: 8.31 (d, J¼7.76 Hz, 2H), 8.02 (t, J¼8.00,
8.00 Hz, 1H), 4.47 (t, J¼6.40, 6.40 Hz, 4H), 1.86 (q, J¼6.80, 6.80,
6.80 Hz, 4H), 1.05 (t, J¼7.20, 7.20 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d
ppm: 164.6, 148.5, 138.3, 127.7, 68.8, 21.9, 10.4. TOF MS: m/z¼252.1
[MþH]þ.
data were collected using Rigaku Saturn diffractometer with
ꢀ
graphite monochromated Mo K
a
radiation (
l
¼0.71073 A). All cal-
culations were performed using the CrystalStructure crystallo-
graphic software package except for refinement, which was
performed using SHELXL-97.
4.2.4. 2-(3-Chloro-1-propoxycarbonyl)-pyridine-6-carboxylic acid (3d)
and 2-(3-chloro-1-propyl)-pyridine-2,6-dicarboxylate
(4d). Application to chromatography using CH2Cl2/ethyl acetate/
acitic acid (100:100:1 and 10:1) as the eluents afforded the product
3d (1.66 g, 6.82 mmol, yield: 76%) as a yellow solid and 4d as a white
solid (0.72 g, 2.25 mmol, yield¼25%). For 3d: 1H NMR (400 MHz,
CDCl3) ppm: 8.44 (d, J¼7.60 Hz, 1H), 8.37 (d, J¼7.60 Hz, 1H), 8.137 (t,
J¼7.76 and 7.76 Hz, 1H), 4.61 (t, J¼6.16 and 6.16 Hz, 2H), 3.72 (t,
J¼6.28 and 6.28 Hz, 2H), 2.31 (quintet, J¼6.20, 6.24, 6.24, 6.20 Hz,
2H). 13C NMR (100 MHz, CDCl3) ppm: 163.7, 146.8, 146.7, 139.8, 139.8,
4.2. Synthesis of 2-alkoycarbonyl-pyridine-6-carboxylic acid
(3) and alkoyl pyridine-2,6-dicarbolic ester (4)
A general synthetic procedure is as follows. Pyridine-2,6-
dicarboxylic acid (1, 1.5 g, 8.98 mmol) was mixed with 24 mL of
SOCl2. The resulted mixture was refluxed for 3 h. The excess of

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H. Zhu et al. / Tetrahedron 67 (2011) 8458e8464
128.9, 127.1, 63.3, 41.3, 31.6. TOF MS: m/z¼242.1 [MꢀH]ꢀ. For 4d: 1H
NMR (400 MHz, CDCl3) ppm: 8.29 (d, J¼7.76 Hz, 2H), 8.02 (t, J¼8.00,
8.00 Hz, 1H), 4.59 (t, J¼6.12, 6.12 Hz, 2H), 3.73 (t, J¼6.28 and 6.28 Hz,
2H), 2.31 (quintet, J¼6.20, 6.24, 6.24, 6.20 Hz, 2H). 13C NMR
(100 MHz, CDCl3) ppm: 164.5, 148.3, 138.8,128.0, 62.9, 41.2, 31.5. TOF
MS: m/z¼320.1 [MþH]þ.
(100 MHz, CDCl3) ppm: 164.0, 162.1, 149.2, 147.7, 138.9, 128.5, 126.3,
52.2. MALDI-TOF MS: m/z¼344.2 [MþH]þ and 366.2 [MþNa]þ.
Trimer 7a was obtained in a yield of 30% with CH2Cl2/ethyl
acetate¼5:1 as the eluents. 1H NMR (300 MHz, CDCl3) ppm: 13.02
(s, 2H), 8.62 (d, J¼7.75 Hz, 2H), 8.52 (d, J¼6.80 Hz, 2H), 8.28 (t,
J¼7.20, 7.20 Hz, 1H), 8.05 (dd, J¼7.00, 7.16 Hz, 4H), 3.55 (s, 6H). 13C
NMR (100 MHz, CDCl3) ppm: 163.2, 161.7, 161.3, 149.2, 148.4, 146.0,
140.3, 139.1, 128.4, 127.2, 125.8, 52.7. ESI MS: m/z¼492.1 [MþH]þ
and 514.1 [MþNa]þ.
4.3. Synthesis of 2-alkoxycarbonyl-pyridine-6-carboxamide
(5)
4.4.2. Dimer 6b and trimer 7b. Dimer 6b was isolated using CH2Cl2/
ethyl acetate¼40:1 as the eluents in a yield of 54%. 1H NMR
(400 MHz, CDCl3) ppm: 12.96 (s, 1H), 8.53 (d, J¼7.77 Hz, 2H), 8.35
(d, J¼7.73 Hz, 2H), 8.10 (t, J¼7.79, 7.79 Hz, 2H), 4.61 (q, J¼7.10, 7.10,
7.09 Hz, 4H), 1.49 (t, J¼7.11, 7.11 Hz, 6H). 13C NMR (100 MHz, CDCl3)
ppm: 164.0, 162.1, 149.2, 147.7, 138.9, 128.5, 126.3, 61.0, 14.3. MALDI-
TOF MS: m/z¼372.2 [MþH]þ, 394.2 [MþNa]þ, and 410.2 [MþK]þ.
Trimer 7b was obtained in a yield of 37% with CH2Cl2/ethyl
acetate¼5:1 as the eluents. 1H NMR (300 MHz, CDCl3) ppm: 13.04
(s, 2H), 8.61 (d, J¼7.75 Hz, 2H), 8.49 (dd, J¼7.00, 1.09 Hz, 2H), 8.27 (t,
J¼7.75, 7.75 Hz, 1H), 8.02 (q, J¼7.99, 7.86, 7.86 Hz, 4H), 3.96 (q,
J¼7.09, 7.09, 7.09 Hz, 4H), 1.19 (t, J¼7.10, 7.10 Hz, 6H). 13C NMR
(100 MHz, CDCl3) ppm: 162.6, 161.7, 161.3, 149.3, 148.4, 146.4, 140.2,
138.9, 128.3, 127.2, 125.7, 60.9, 14.0. ESI MS: m/z¼520.2 [MþH]þ,
542.3 [MþNa]þ, and 558.4 [MþK]þ.
A general synthetic procedure is as follows. Compound 3
(2.16 mmol) was mixed with 20 mL of SOCl2. The resulted mixture
was refluxed for 3 h. The excess of SOCl2 was then removed under
vacuum. The resulted white solid was then dissolved in 50 mL of
CH2Cl2. To which ammon gas was bubbled inside for 2 h. Then the
solution was washed with 1 M hydrochloric acid aqueous solution,
dilute Na2CO3 aqueous solution, and water each for twice. Removal
of the solvent afforded 5.
4.3.1. 2-Methoxycarbonyl-pyridine-6-carboxamide (5a). This prod-
uct was obtained as a yellow solid in a yield of 80%. 1H NMR
(400 MHz, CDCl3) ppm: 8.40 (d, J¼7.60 Hz, 1H), 8.26 (d, J¼7.60 Hz,
1H), 8.02 (t, J¼7.60, 7.60 Hz, 1H), 7.94 (s, 1H), 5.76 (s, 1H), 4.01 (s,
3H). 13C NMR (100 MHz, CDCl3)
d ppm: 165.9, 164.5, 149.9, 147.2,
138.5, 127.4, 125.4, 51.8. TOF MS: m/z¼181.0 [MþH]þ.
4.4.3. Dimer 6c and trimer 7c. Dimer 6c was isolated using CH2Cl2/
ethyl acetate¼40:1 as the eluents in a yield of 42%. 1H NMR
(400 MHz, CDCl3) ppm: 12.98 (s, 1H), 8.54 (d, J¼7.77 Hz, 2H), 8.37
(d, J¼7.73 Hz, 2H), 8.10 (t, J¼7.79, 7.79 Hz, 2H), 4.50 (t, J¼6.00,
6.00 Hz, 4H), 1.78 (q, 7.20, 7.20, 7.20 Hz, 4H), 0.98 (t, J¼7.20, 7.20 Hz,
6H). 13C NMR (100 MHz, CDCl3) ppm: 164.0, 162.1, 149.2, 147.7,
138.9, 128.5, 126.3, 68.8, 21.9, 10.4. MALDI-TOF MS: m/z¼400.2
[MþH]þ, 422.2 [MþNa]þ, and 438.2 [MþK]þ.
4.3.2. 2-Ethoxycarbonyl-pyridine-6-carboxamide (5b). This product
was obtained as a yellow solid in a yield of 95%. 1H NMR (400 MHz,
CDCl3) ppm 8.39 (d, J¼7.79 Hz, 1H), 8.25 (d, J¼7.78 Hz, 1H), 8.02 (t,
J¼7.79, 7.79 Hz, 1H), 7.98 (s, 1H), 6.02 (s, 1H), 4.48 (q, J¼7.14, 7.14,
7.13 Hz, 2H), 1.45 (t, J¼7.14, 7.14 Hz, 3H). 13C NMR (100 MHz, CDCl3)
ppm: 165.9, 164.4, 149.8, 147.1, 138.4, 127.5, 125.4, 62.0, 14.3. TOF
MS: m/z¼195.0 [MþH]þ.
Trimer 7c was obtained in a yield of 50% with CH2Cl2/ethyl
acetate¼5:1 as the eluents. 1H NMR (300 MHz, CDCl3) ppm: 13.04 (s,
2H), 8.62 (d, J¼7.75 Hz, 2H), 8.50 (dd, J¼7.00, 1.09 Hz, 2H), 8.27 (t,
J¼7.75, 7.75 Hz,1H), 8.05(m, J¼6.80, 8.00, 7.20 Hz, 4H), 3.85(t, J¼6.00,
6.00 Hz, 4H),1.58 (q, J¼7.20, 7.20, 7.20 Hz, 4H), 0.88 (t, J¼7.20, 7.20 Hz,
6H). 13C NMR (100 MHz, CDCl3) ppm: 162.5,161.8,161.3,149.3,148.4,
146.3, 140.3, 138.8, 128.2, 127.1, 125.6, 67.3, 21.7, 10.2. ESI MS: m/
z¼548.2 [MþH]þ, 570.2 [MþNa]þ, and 586.2 [MþK]þ.
4.3.3. 2-(n-Propoxycarbonyl)-pyridine-6-carboxamide
(5c). This
product was obtained as a yellow solid in a yield of 86%. 1H NMR
(400 MHz, CDCl3) ppm: 8.39 (d, J¼7.60 Hz, 1H), 8.25 (d, J¼7.60 Hz,
1H), 8.02 (t, J¼7.60, 7.60 Hz, 1H), 7.96 (br s, 1H), 5.71 (br s, 1H), 4.37
(t, J¼6.40, 6.40 Hz, 2H), 1.84 (q, 6.80, 6.80, 6.80 Hz, 2H), 1.05 (t,
J¼7.20, 7.20 Hz, 3H). 13C NMR (100 MHz, CDCl3) ppm: 166.2, 164.3,
150.1, 148.5, 138.5, 127.6, 125.8, 68.8, 21.9, 10.4. TOF MS: m/z¼209.0
[MþH]þ.
4.4.4. Dimer 6d and trimer 7d. Dimer 6d was isolated using CH2Cl2/
ethyl acetate¼20:1 as the eluents in a yield of 2%. 1H NMR
(400 MHz, CDCl3) ppm: 12.88 (s, 1H), 8.55 (d, J¼8.00 Hz, 2H), 8.36
(d, J¼8.00 Hz, 2H), 8.12 (t, J¼8.00 and 8.00 Hz, 1H), 4.70 (t, J¼6.40
and 6.40 Hz, 4H), 3.71 (t, J¼6.40 and 6.40 Hz, 4H), 2.35 (quintet,
J¼6.40, 6.40, 6.40, 6.40 Hz, 4H). 13C NMR (100 MHz, CDCl3) ppm:
163.8, 162.1, 149.3, 147.2, 139.1, 128.7, 126.6, 63.2, 41.4, 31.6. TOF MS:
m/z¼467.1 [M] and 490.2 [100%] [MþNa]þ.
4.3.4. 2-(3-Chloro-1-propoxycarbonyl)-pyridine-6-carboxamide
(5d). This product was obtained as a yellow solid in a yield of 90%.
1H NMR (400 MHz, CDCl3) ppm: 8.41 (d, J¼7.76 Hz, 1H), 8.25 (d,
J¼7.76 Hz, 1H), 8.03 (t, J¼7.80 and 7.80 Hz, 1H), 7.92 (br s, 1H), 5.68
(br s, 1H), 4.58 (t, J¼6.04 and 6.04 Hz, 2H), 3.72 (t, J¼6.28 and
6.28 Hz, 2H), 2.29 (quintet, J¼6.20, 6.24, 6.24, 6.20 Hz, 2H). 13C NMR
(100 MHz, CDCl3) ppm: 166.1, 164.4, 150.0, 148.4, 138.4, 127.6, 125.7,
62.2, 41.3, 31.6. TOF MS: m/z¼243.0 [MþH]þ.
Trimer 7d was isolated as a white solid by using CH2Cl2/ethyl
acetate¼20:1 as the eluents in
a yield of 95% (278.7 mg,
4.4. Synthesis of dimer and trimer
0.474 mmol). 1H NMR (400 MHz, CDCl3) ppm: 13.02 (s, 2H), 8.62 (d,
J¼8.00 Hz, 2H), 8.53 (d, J¼7.6 Hz, 2H), 8.27 (t, J¼8.00 and 7.60 Hz,
1H), 8.06 (t, J¼8.00 and 7.60 Hz, 2H), 7.99 (d, J¼8.0 Hz, 2H), 4.06 (t,
J¼6.20 and 6.16 Hz, 4H), 3.51 (t, J¼6.24 and 6.24 Hz, 4H), 2.03
(quintet, J¼6.00, 6.28, 6.28, 6.00 Hz, 4H). 13C NMR (100 MHz, CDCl3)
ppm: 162.4, 161.8, 161.5, 149.6, 148.5, 146.0, 140.4, 139.2, 128.4,
127.4, 126.0, 62.8, 40.9, 31.3. TOF MS: m/z¼615.1 [M], 638.2 [100%]
[MþNa]þ, and 654.2 [MþK]þ.
A typical procedure is described as follows. Dichloride (2) was
obtained by refluxing 1 (2.5 mmol) in 30 mL of SOCl2 for 3 h. To the
resulted white solid of 2, 50 ml of toluene and 1 mmol of 6 were
added and the reaction was allowed to reflux overnight. Then, the
solvent was removed and the resulted residue was applied to
chromatography to afford product 6aed and 7aed.
4.4.1. Dimer 6a and trimer 7a. Dimer 6a was isolated using CH2Cl2/
ethyl acetate¼40:1 as the eluents in a yield of 60%. 1H NMR
(400 MHz, CDCl3) ppm: 12.98 (s, 1H), 8.56 (d, J¼7.77 Hz, 2H), 8.39
(d, J¼7.73 Hz, 2H), 8.11 (t, J¼7.79, 7.79 Hz, 2H), 4.10 (s, 6H). 13C NMR
4.5. Synthesis of dimeric monoamide
4.5.1. Dimer 6d. Compound 3d (233.1 mg, 1.02 mmol) was mixed
with 10 mL of SOCl2. The resulted mixture was refluxed for 3 h. The

H. Zhu et al. / Tetrahedron 67 (2011) 8458e8464
8463
excess of SOCl2 was then removed under vacuum to afford a white
solid, which was mixed with 5d (205.4 mg, 0.85 mmol) and dis-
solved in 40 mL of toluene. The resulted solution was refluxed
overnight. After removal of the solvent, the residue was applied to
chromatography using CH2Cl2/ethyl acetate¼20:1 as the eluents to
afford product 6d (256.3 mg, 0.58 mmol, yield: 68%).
31.1. TOF MS: m/z¼764.1 [M], 786.1 [100%] [MþNa]þ, and 802.1
[MþK]þ.
4.6.2. Pentamer 13. 1H NMR (400 MHz, CDCl3) ppm: 12.38 (s, 2H),
12.31 and (s, 2H), 8.67 (d, J¼6.92 Hz, 2H), 8.53 (d, J¼7.72 Hz, 2H),
8.31 (m, J¼7.60, 6.00, 1.20, 7.60 Hz, 4H), 8.17 (t, J¼8.00 and 7.60 Hz,
2H), 8.13 (6.40, 5.6 Hz, 3 Hz), 8.01 (d, J¼8.00 Hz, 2H), 3.88 (t, J¼6.00
and 6.00 Hz, 4Hꢁ65%), 3.74 (t, J¼5.44 Hz, 4Hꢁ35%), 3.48 (t, J¼6.00
and 6.00 Hz, 4Hꢁ65%), 3.43 (t, J¼5.60, 6.24 Hz, 4Hꢁ35%), 1.94
(quintet, J¼6.00, 5.76Hz, 4H). 13C NMR (100 MHz, CDCl3) ppm:
162.1, 161.8, 160.5, 160.2, 160.0, 148.6, 147.7, 147.4, 145.2, 141.3, 140.3,
139.6, 129.0, 128.4, 127.8, 127.2, 126.3, 65.1, 62.4, 44.3, 40.9, 31.1,
29.8. TOF MS: m/z¼934.1 [MþNa]þ, and 950.2 [MþK]þ.
4.5.2. Dimer monoacid 10. Compound 6d (304 mg, 0.80 mmol) was
dissolved in a mixed solvents of dioxane (50 ml) and water (5 ml),
to which,1 mol/L of NaOH aqueous solution (0.80 ml) was dropwise
added. After stirred for 3 h, the reaction solution was washed with
saturated NaCl solution and water each for twice. The organic layer
was then dried over Na2SO3. After removal of organic solvent, the
residue was applied to chromatography using CH2Cl2/ethyl acetate/
acetic acid¼10:10:1 as the eluents to afford product 10 (164.5 mg,
0.435 mmol, yield: 55%). 1H NMR (400 MHz, CDCl3) ppm: 13.01 (s,
1H), 8.68 (d, J¼7.60 Hz, 1H), 8.59 (d, J¼8.00 Hz, 1H), 8.39 (d,
J¼8.00 Hz, 1H), 8.26 (t, J¼7.60 and 7.60 Hz, 1H), 8.17 (t, J¼8.00 and
8.00 Hz, 1H), 4.72 (t, J¼6.24 and 6.24 Hz, 2H), 3.70 (t, J¼6.40 and
6.40 Hz, 2H), 2.33 (quintet, J¼6.24, 6.24, 6.24, 6.24 Hz, 2H). 13C NMR
The splitting of the imide hydrogen and 3-Cl-1-propyl hydro-
gens for the tetrameric and pentameric PIOs may be due to the
different local conformations of 3-Cl-1-propyl terminal after for-
mation of helical structure.
Acknowledgements
(100 MHz, CDCl3)
d ppm: 164.5, 164.3, 163.7, 163.5, 148.5, 148.4,
This work was financially supported by NSFC (Nos. 20872145
and 20973182), the Chinese Academy of Sciences, Projects 973
(2011CB400808 and 2007CB936401).
148.2, 148.1, 139.4, 139.3, 138.9, 138.8, 128.3, 128.0, 63.0, 41.4, 31.4.
TOF MS: m/z¼390.1 [MꢀH]ꢀ.
4.5.3. Dimer monoamide 11. Compound 10 (287.8 mg, 0.77 mmol)
was dissolved in SOCl2 (5 ml). The resulted mixture was refluxed for
3 h. The excess of SOCl2 was then removed under vacuum. The
resulted white solid was then dissolved in 50 mL of CH2Cl2. To
which ammon gas was bubbled inside for 2 h. Then the solution
was washed with 1 M hydrochloric acid aqueous solution, dilute
Na2CO3 aqueous solution, and water each for twice. Removal of the
solvent afforded product 10 (258.3 mg, 0.6857 mmol, yield: 90%).
1H NMR (400 MHz, CDCl3) ppm: 13.01 (s, 1H), 8.68 (d, J¼7.60 Hz,
1H), 8.59 (d, J¼8.00 Hz, 1H), 8.39 (d, J¼8.00 Hz, 1H), 8.26 (t, J¼7.60
and 7.60 Hz,1H), 8.17 (t, J¼8.00 and 8.00 Hz,1H), 7.92 (br s,1H), 5.68
(br s, 1H), 4.72 (t, J¼6.24 and 6.24 Hz, 2H), 3.70 (t, J¼6.40 and
6.40 Hz, 2H), 2.33 (quintet, J¼6.24, 6.24, 6.24, 6.24 Hz, 2H). 13C NMR
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.09.006. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
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~
Espana, E.; Luis, S. V.; Miravet, J. F. J. Am. Chem. Soc. 2003, 125, 6677e6686; (e)
Boal, A. K.; Guryanov, I.; Moretto, A.; Crisma, M.; Lanni, E. L.; Toniolo, C.;
Grubbs, R. H.; O’Leary, D. J. J. Am. Chem. Soc. 2007, 129, 6986e6987; (f) Ferraz,
R.; Gomes, J. R. B.; de Oliveira, E.; Moreira, R.; Gomes, P. J. Org. Chem. 2007, 72,
4189e4197; (g) Zhu, H.; Guan, Z.; Zhan, C. Chin J. Org. Chem. 2010, 30,
1716e1720.
ꢁ
14. (a) Jiang, H.; Leger, J. M.; Huc, I. J. Am. Chem. Soc. 2003, 125, 3448e3449; (b)
ꢁ
Sanchez-García, D.; Kauffmann, B.; Kawanami, T.; Ihara, H.; Takafuji, M.;
Delville, M.-H.; Huc, I. J. Am. Chem. Soc. 2009, 131, 8642e8648.
15. (a) Hu, H.-Y.; Xiang, J.-F.; Yang, Y.; Chen, C.-F. Org. Lett. 2008, 10, 1275e1278; (b)
Hu, H.-Y.; Xiang, J.-F.; Yang, Y.; Chen, C.-F. Org. Lett. 2008, 10, 69e72.
16. (a) Bao, C.; Kauffmann, B.; Gan, Q.; Srinivas, K.; Jiang, H.; Huc, I. Angew. Chem.,
22. Crystal data for 7a: crystallization solvent/precipitant: DMF/ethyl ether, tri-
ꢀ
clinic, space group Pꢀ1, colorless, (a) 7.9371 (1), (b) 9.1064 (18), (c) 15.505 (3) A,
Int. Ed. 2008, 47, 4153e4156; (b) Gan, Q.; Bao, C.; Kauffmann, B.; Grelard, A.;
a
¼76.25 (3)ꢂ,
g
¼87.23 (3)ꢂ,
b
¼83.28 (3)ꢂ, T¼173 (2) K, Z¼2, GOF¼1.090. The
(I))¼0.0398, wR2 (all data)¼0.1187.
ꢁ
Xiang, J.; Liu, S.; Huc, I.; Jiang, H. Angew. Chem., Int. Ed. 2008, 47, 1715e1718.
17. (a) Corbin, P. S.; Zimmerman, S. C.; Thiessen, P. A.; Hawryluk, N. A.; Murray, T. J.
J. Am. Chem. Soc. 2001, 123, 10475e10488; (b) Sinkeldam, R. W.; Hoeben, F. J. M.;
Pouderoijen, M. J.; DeCat, I.; Zhang, J.; Furukawa, S.; DeFeyter, S.; Vekemans, J.
A. J. M.; Meijer, E. W. J. Am. Chem. Soc. 2006, 128, 16113e16121; (c) Clayden, J.;
final R indices were R1 (I>2s
23. Crystal data for 7c: crystallization solvent/precipitant: DMF/ethyl ether,
monoclinic, space group P21/c, colorless, (a) 12.728 (3), b) 19.183 (4), (c) 21.427
ꢀ
(4) A,
a
¼90ꢂ,
g
¼90.77 (3)ꢂ,
b
¼90ꢂ, T¼173 (2) K, Z¼8, GOF¼1.197. The final R
indices were R1 (I>2
24. Crystal data for 7d: crystallization solvent/precipitant: DMF/ethyl ether,
s
(I))¼0.0958, wR2 (all data)¼0.1682.
ꢂ
Lemiegre, L.; Morris, G. A.; Pickworth, M.; Snape, T. J.; Jones, L. H. J. Am. Chem.
Soc. 2008, 130, 15193e15202.
18. Garric, J.; Leger, J. M.; Grelard, A.; Ohkita, M.; Huc, I. Tetrahedron Lett. 2003, 44,
monoclinic, space group P21/c, colorless, (a) 11.6507 (14), (b) 17.887 (2), (c) 13.
¼90ꢂ,
b
¼104.953 (8)ꢂ, T¼173 (2) K, Z¼4, GOF¼1.106. The final
(I))¼0.0534, wR2 (all data)¼0.1445.
ꢀ
ꢁ
6683 (17) A,
a
¼g
1421e1424.
R indices were R1 (I>2
s